CN116648502A - Methods and reagents for characterizing CAR T cells for treatment - Google Patents
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Abstract
Provided herein are methods, kits, and reagents for analyzing properties of engineered immune cells, such as CAR T cells. For example, provided herein are methods of determining the number or percentage of tcrαβ+ CAR T cells remaining in an allogeneic CAR T cell drug, as well as characterizing other important attributes of the CAR T cell drug.
Description
Cross Reference to Related Applications
The present application claims U.S. provisional application 63/125,149 filed 12/14 in 2020; and U.S. provisional application 63/265,086 filed on 7 at 12/2021, the contents of both of which are hereby incorporated by reference in their entirety.
Sequence listing
The present application contains a sequence listing that is electronically submitted in ASCII format and hereby incorporated by reference in its entirety. The ASCII copy was created AT 2021, 12 months 10, named AT-037_03wo_sl.txt, and was 8,915 bytes in size.
Background
Chimeric Antigen Receptor (CAR) T cell therapies have been unprecedented successful, but the preparation of CAR T cells also faces unprecedented challenges. Compared to CAR T cells derived from patient's own cells (autologous CAR T cells), CAR T cells derived from allogeneic donor cells (allogeneic CAR T cells) can be produced as off-the-shelf products, at lower cost, and with simpler manufacturing process. Despite these advantages, unique challenges remain in allogeneic CAR T cell production. In an allogeneic setting, one way to alleviate graft versus host disease (GvHD) is to disrupt TCR a and/or TCR β genes that reduce or eliminate functional TCR a β signaling in donor cells. The engineered CAR T cells are treated to remove or reject any remaining unmodified tcrαβ positive cells and any remaining tcrαβ positive cells in the drug substance or final drug product are determined.
Layered gating applied to semi-quantitative flow cytometry allows detailed analysis of heterogeneous cell populations. Thus, this method is often used analytically to provide CMC (chemical, manufacturing and control) technical information for complex engineered cell therapies, such as CAR T cells, during or after manufacturing. However, challenges exist when using these methods in a highly simplified manufacturing environment that meets cGMP (current good manufacturing practice) requirements. One of the sources of challenges is the differentiation of the starting cells. For example, the level of tcrαβ positive rate varies from donor to donor during allogeneic CAR T cell preparation, which makes gating settings difficult. Improper tcrαβ gating settings can lead to under-reporting or over-reporting of tcrαβ positive T cells, which may lead to increased risk of GvHD in the patient or increased risk of rejecting appropriate T cell drugs, respectively. Furthermore, compatible reagents for TCR knockdown and detection may not always be available.
Furthermore, it is desirable to determine other properties of complex engineered cell therapies (such as CAR T drugs) in a manner that is suitable for a highly simplified commercial manufacturing environment. Thus, there is a need for improved methods to analyze and characterize important attributes of composite cytotherapeutic drugs in manufacturing environments, particularly in GMP environments.
Technical Field
The present disclosure relates to methods and reagents for analyzing engineered immune cells, including those comprising Chimeric Antigen Receptors (CARs), i.e., CAR T cells. For example, the present disclosure relates to, among other things, methods of determining the number or percentage of tcrαβ+ CAR T cells remaining in an allogeneic CAR T cell drug and methods of characterizing other properties of CAR T cells.
Disclosure of Invention
The present disclosure relates to methods and reagents for analyzing engineered immune cells, including those comprising Chimeric Antigen Receptors (CARs).
Provided herein are methods, reagents, and kits for analyzing and characterizing engineered immune cells (such as CAR T cells) during or after the manufacturing process. For example, provided herein are methods, reagents, and kits for analyzing the potency or versatility and/or other attributes of prepared CAR T cells, including the number or percentage of tcrαβ+ T cells remaining in the prepared allogeneic CAR T cells.
In one aspect, the present disclosure provides a method of analyzing a population of immune cells, wherein the population of immune cells has been engineered to introduce one or more genetic modifications at the tcra and/or tcrp loci that reduce or impair tcra surface expression, the method comprising the steps of: (a) Obtaining or measuring viable cd45+ cells from the population of immune cells; (b) Obtaining or measuring a cd5+/cd3+ cell from the cell described in step (a); (c) Measuring or determining the percentage or number of cd3+/tcrγδ -cells from the cells described in step (b), wherein the percentage or number of cd3+/tcrγδ -cells described in step (c) represents the percentage or number of tcrαβ+ T cells present in the immune cell population. In some embodiments, the one or more genetic modifications are at the tcra locus. In some embodiments, the one or more genetic modifications are at the TRAC locus (TCR alpha chain constant region).
In another aspect, the present disclosure provides a method of measuring the percentage or number of tcrαβ+ T cells in an immune cell population, wherein the immune cell population has been engineered to introduce one or more genetic modifications at the tcrαand/or tcrβ loci that reduce or impair tcrαβ surface expression, the method comprising the steps of: (a) Obtaining or measuring viable cd45+ cells from the population of immune cells; (b) Obtaining or measuring a cd5+/cd3+ cell from the cell described in step (a); and (c) measuring or determining the percentage or number of cd3+/tcrγδ -cells from the cells described in step (b), wherein the percentage or number of cd3+/tcrγδ -cells described in step (c) represents the percentage or number of tcrαβ+ T cells in the immune cell population. In some embodiments, the one or more genetic modifications are at the tcra locus. In some embodiments, the one or more genetic modifications are at the TRAC locus.
In some embodiments, the population of immune cells has been engineered to express a CAR. In some embodiments, the population of immune cells is CAR T cells. In some embodiments, the immune cell population is Peripheral Blood Mononuclear Cells (PBMCs). In some embodiments, the immune cell population is a cd4+ and/or cd8+ T cell population. In some embodiments, the percentage or number of tcrαβ+ T cells is determined by subtracting the percentage or number of cd3+/tcrγδ+ cells from the population of cd5+/cd3+ cells described in step (b). In certain embodiments, the method further comprises the step of determining cd3+/tcrγδ+ cells. In some embodiments, the CAR T cells are allogeneic CAR T cells.
In another aspect, the present disclosure provides a method of analyzing CAR T cells, the method comprising the step of measuring surface CD107 of the CAR T cells after antigen stimulation, wherein an increased level of surface CD107 compared to the level prior to antigen stimulation is indicative of a multifunctional CAR T cell. In some embodiments, the increase in the level of surface CD107 is a percentage increase or an average/median fluorescence intensity increase of surface CD 107. In certain embodiments, the multifunctional CAR T cells secrete higher levels of tnfα after antigen stimulation than non-multifunctional CAR T cells under the same conditions. In certain embodiments, the multifunctional CAR T cells secrete higher levels of IL2 after antigen stimulation than non-multifunctional CAR T cells under the same conditions. In certain embodiments, the multi-functional CAR T cells secrete higher levels of ifnγ after antigen stimulation than non-multi-functional CAR T cells under the same conditions. In some embodiments, the CAR T cells have been engineered to introduce one or more genetic modifications at the tcra and/or tcrp loci that reduce or impair tcra surface expression. In some embodiments, the one or more genetic modifications are at the tcra locus. In some embodiments, the method does not require a step of measuring one or more effector cytokines. In some embodiments, the method further comprises the step of measuring one or more cytokines selected from the group consisting of: INFγ, TNF α, IL2, GM-CSF, CXCL1, IL-1B, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-17, IL-21, IL-22, IL-23, CXCL11, mip1a, mip1B, mip3a, TNFb, perforin, granzyme A, granzyme B, granzyme H, CCL, IP-10, CCL5, TGFb, sCD137, sCD40L, MCP-1 and MCP-4. In some embodiments, the CAR T cells are stimulated by co-culturing the CAR T cells with target cells that express an antigen of the CAR. In some embodiments, wherein the target cell is a tumor cell. In some embodiments, the level of surface CD107 is measured by flow cytometry. In some embodiments, the CD107 is CD107a and/or CD107b. In some embodiments, CD107 is measured about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours after initiation of antigen activation. In some embodiments, CD107 is measured about 4-8 hours, about 4-6 hours, about 6-8 hours, about 6-10 hours, or about 8-10 hours after antigen activation begins. In some embodiments, the CAR T cell is an autologous CAR T cell. In some embodiments, the CAR T cells are allogeneic CAR T cells.
In some embodiments of any aspect of the disclosure, the method further comprises the step of measuring car+ T cells. In some embodiments, the percentage or number of car+ T cells is measured using an anti-idiotype antibody. In some embodiments, the population of immune cells is obtained from a healthy donor. In some embodiments, the CAR T cells are allogeneic CAR T cells.
In some embodiments, the immune cell expresses a CAR that has specificity for egfrvlll, WT-1, CD20, CD23, CD30, CD38, CD33, CD133, MHC-WT1, TSPAN10, MHC-PRAME, liv1, ADAM10, chra 2, leY, NKGD2D, CS1, CD44v6, ROR1, claudin) -18.2, muc17, fapα, ly6G6D, c6orf23, G6D, MEGT1, NG25, CD19, BCMA, FLT3, CD70, DLL3, CD52, or CD 34. In some embodiments, the CAR comprises an antigen binding domain that targets egfrvlll, WT-1, CD20, CD23, CD30, CD38, CD33, CD133, MHC-WT1, TSPAN10, MHC-PRAME, liv1, ADAM10, chra 2, leY, NKGD2D, CS1, CD44v6, ROR1, tight junction protein (Claudin) -18.2, muc17, fapα, ly6G6D, c orf23, G6D, MEGT1, NG25, CD19, BCMA, FLT3, CD70, DLL3, CD52, or CD 34.
In some embodiments, the method further comprises the step of filling the population of immune cells into one or more containers, provided that the number or percentage of tcrαβ+ T cells does not exceed a predetermined threshold and/or if the population of immune cells comprises multi-functional CAR T cells, optionally not less than a predetermined threshold, as determined herein. In some embodiments, the predetermined threshold for the percentage of tcrαβ+ T cells is about 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. In some embodiments, the predetermined threshold for the percentage of multi-functional CAR T cells is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of the total CAR T cell population.
In another aspect, the present disclosure provides a method of preparing a cell-based pharmaceutical product comprising an engineered immune cell, the method comprising the steps of analyzing an immune cell population as described herein, and filling the immune cell population into one or more containers, provided that the number or percentage of tcrαβ+ T cells does not exceed a predetermined threshold and/or if the immune cell population comprises multi-functional CAR T cells that are optionally not less than the predetermined threshold.
In another aspect, the present disclosure provides a kit or article of manufacture for analyzing CAR T cells, the kit or article of manufacture comprising one or more reagents for detecting CD3 and/or tcrγδ.
In some embodiments, the kit or article further comprises one or more reagents for detecting CD45, CD5, CD52, CD107 (CD 107a and/or CD107 b) and/or CAR. In some embodiments, the one or more reagents comprise an antibody, optionally conjugated with a detectable label. In some embodiments, the detectable label is selected from the group consisting of: fluorescent labels, photochromic compounds, protein fluorescent labels, magnetic labels, radioactive labels and haptens. In some embodiments, the fluorescent label is selected from the group consisting of: atto dye, alexafluor dye, quantum dot, hydroxycoumarin, aminocoumarin, methoxycoumarin, cascade Blue (Cascade Blue), pacific Blue (Pacific Blue), pacific Orange (Pacific Orange), lucifer Yellow (Lucifer Yellow), NBD, R-Phycoerythrin (PE), PE-Cy5 conjugate, PE-Cy7 conjugate, red 613, perCP, truRed, fluorX, fluorescein, BODIPY-FL, cy2, cy3B, cy3.5, cy5, cy5.5, cy7, TRITC, X-rhodamine, lissamine rhodamine B (Lissamine Rhocamine B), texas Red (Texas Red), allophycocyanin (APC), APC-Cy7 conjugate, ind-1, fluo-3 Fluo-4, DCFH, DHR, SNARF, GFP (Y66H mutation), GFP (Y66F mutation), EBFP2, blue copper (Azurite), GFPuv, T-Sapphire (T-Sapphire), sky Blue (Cerulean), mCFP, mTurquoise2, ECFP, cyPet, GFP (Y66W mutation), mKeima-Red, tagCFP, amCyan1, mTFP1, GFP (S65A mutation), mi Duli assort (Midorishi Cyan), wild GFP, GFP (S65C mutation), turboGFP, tagGFP, GFP (S65L mutation), emerald (Emerald), GFP (S65T mutation), EGFP, AZami Green (Azami Green), zsGreen1, tagYFP, EYFP, topaz, venus, mCitrine, YPet, turboYFP, zsYellow, coasabira Orange (Kusabira Orange), mOrange, allophycocyanin (APC), mKO, turboRFP, tdTomato, tagRFP, dsRed monomer, dsRed2 ("RFP"), mStrawberry, turboFP, 82602, asRed2, mRFP1, J-Red, R-phycoerythrin (RPE), B-phycoerythrin (BPE), mCherry, hcRed, katusha, P3, polymethine chlorophyll (PerCP), mKate (TagFP 635), turboFP635, mPlum, and mrespberary. In some embodiments, the one or more reagents are used in flow cytometry.
Drawings
FIG. 1 shows the quantitative results of flow cytometric analysis of the residual percentage of TCRαβ+ cells gated by TCR cutoff set by donor cells determined prior to removal of TCRαβ from either donor 1 (ACC-1: assay control cells from donor 1) or donor 2 (ACC-2: assay control cells from donor 2). Results are provided in triplicate and Standard Deviation (SD). See also table 2.ALLO-501A: CD19 CAR T without rituximab suicide switch.
Figures 2A and 2B depict plots of flow cytometry analysis showing flow gating in TCR ablated CAR T cells (figure 2A) and correlation between cd3+ intracellular staining and cd5+ surface staining (figure 2B). See also table 3.
Panels a-I of fig. 3 show the workflow of continuous FACS analysis of CD19 CAR T cells for determining the remaining percentage of tcrab+ T cells after TCR ablation using internal biological gates, and the level of CD107a after activation of CD19 positive target cells.
Figure 4 shows the results of expression of various effector cytokines and CAR expression in each CAR T cell population when CAR T cells were co-cultured with CD19-KG1a cells, cd19+daudi cells, or when CAR T cells were incubated with PMA (phorbol myristate acetate) and ionomycin (calcium ionophore) (as positive control).
FIG. 5A shows the correlation between CD107a and IFNg, IL2 and TNFa in each CAR T cell subset co-cultured with CD19-KG1a cells or CD19+Daudi cells. Figures 5B-5D show the results of further analysis of each cytokine in CAR T cells upon antigen activation: identification of CD5+/CD45+ cells (i.e., T cells, FIG. 5B); division of CAR αβ+ and tcr+, ifng+, il2+, tnfa+ or cd107a+ staining in the cd5+/cd45+ population (fig. 5C); and in the cd5+/cd45+ population, CD107a staining was consistent with each of IFNg, IL2, and TNFa (fig. 5D).
FIG. 6 shows the results of analysis of the induction of individual effector cytokines (IL 2, TNFa and/or IFNg) or combinations of effector cytokines from CD107a+ or CD107a-CAR+ cells (connected by straight lines as shown in the figure) co-cultured with CD19-KG1a cells or CD19+Daudi cells. ALLO-501 and ALLO-501A: CD19CAR T with or without rituximab suicide switch, respectively.
Figures 7A-7B show the correlation of surface expression of CD107A with intracellular staining of two or three cytokines (i.e., tnfα, IL2, and ifnγ (figure 7A)) or all combinations of two of the cytokines (i.e., tnfα, IL2, and ifnγ (figure 7B)) in anti-CD 19CAR T (ALLO-501A) or non-CD 19CAR (CAR B) after co-culture for 6 hours in the presence (filled symbols) or absence (open symbols) of corresponding target positive cells.
Detailed Description
The present disclosure relates to methods and reagents for analyzing engineered immune cells, including those comprising Chimeric Antigen Receptors (CARs).
Provided herein are methods and reagents for analyzing and/or characterizing engineered immune cells, including, but not limited to, CAR T cells, e.g., allogeneic CAR T cells for immunotherapy. The processes and reagents disclosed herein allow for better characterization of CAR T cells in a cGMP (current good manufacturing practice) compliant manufacturing environment. Also provided herein are processes, workflows, kits, articles of manufacture, and reagents that allow for reliable, scalable, and convenient analysis of key attributes of CAR T drugs. The processes and/or reagents disclosed herein, when employed as a set of standardized parameters and analysis procedures, may further simplify the commercial manufacturing process, quality control, and/or documentation facilitating regulatory scrutiny.
The terms "a" and "an" as used herein are used to denote one or more than one. For example, reference to "a cell" or "an antibody" refers to "a cell(s)" or "an antibody(s)".
In one aspect, the present disclosure provides a method of analyzing or characterizing immune cells, particularly allogeneic immune cells, such as allogeneic CAR T cells for immunotherapy. In particular, the present disclosure provides a method of analyzing an immune cell population, wherein the immune cell population has been engineered to introduce one or more genetic modifications at the tcra and/or tcrp loci that reduce or impair tcra surface expression, the method comprising the steps of: (a) Obtaining or measuring viable cd45+ cells from the population of immune cells; (b) Obtaining or measuring a cd5+/cd3+ cell from the cell described in step (a); and (c) measuring or determining the percentage or number of cd3+/tcrγδ -cells from the cells described in step (b), wherein the percentage or number of cd3+/tcrγδ -cells described in step (c) represents the percentage or number of residual tcrαβ+ T cells present in the immune cell population.
T cell receptors are antigen receptor molecules that form complexes on the surface of T cells and are responsible for recognizing antigens presented by MHC molecules to T cells, the interaction of which can cause activation of T cells and an immune response to the antigen. Human T cell receptors are heterodimers consisting of two transmembrane heterodimeric glycoprotein chains, the α and β chains, each having two domains, which are linked by disulfide bonds. Instead, a small subset of T cells express the tcrγδ complex. Because of the short cytoplasmic tail of TCRs, it is not directly signaling when bound to peptide-MHC complexes. In contrast, TCRs are associated with a group of signaling molecules collectively known as CD3, which transmit intracellular signals when the TCRs bind to peptide-MHC complexes. The interaction of tcrαβ on the surface of allogeneic T cells (i.e., T cells from a donor) with host MHC molecules can produce GvHD. Thus, one important strategy for allogeneic T cell therapy is to generate tcrαβ -T cells from an allogeneic source, such as for allogeneic CAR T cell therapy.
CD3 consists of one gamma and delta and two epsilon molecules, both of which share some limited sequence homology in the extracellular domain with the immunoglobulin domain. These molecules have a small cytoplasmic domain and a transmembrane domain with negatively charged residues. In the membrane, these negatively charged residues form a salt bridge with positively charged residues in the transmembrane region of the TCR. The TCR-CD3 receptor complex is formed by two other invariant proteins ζ and η, which form dimers linked by disulfide bonds. Thus, on the surface of T cells, the TCR-CD3 complex is represented as an alpha beta (or less common gamma delta) heterodimer, associated with CD3 gamma epsilon and CD3 delta epsilon dimers, and intracellular zeta homodimers or zeta heterodimers. It is believed that CD3 surface expression may also be eliminated if TCR expression is disrupted.
As used herein, unless specifically indicated, the terms "tcr+", "TCR," "TCR wild-type," "TCR αβ wild-type," "TCR αβ+" or "TCR αβ," when used in reference to a cell or population of cells, include cell populations generated using the methods provided in the present disclosure, refer to cells that express at least endogenous TCR αβ heterodimers, although one or more components of the CD3 complex may or may not be expressed on the cell surface.
As used herein, the terms "TCR," "TCR knockout," or "TCR αβ -" when used in reference to a cell or population of cells, including the population of cells produced using the methods provided in the present disclosure, refer to cells that lack at least TCR αβ heterodimers, although one or more components of the CD3 complex may or may not be expressed on the cell surface.
In some embodiments, the TCR-cells have been genetically modified, e.g., engineered to introduce one or more genetic modifications at the TCR α and/or TCR β chains to reduce or impair expression of TCR α β heterodimers on the cell surface. In some embodiments, one or more genetic modifications are introduced at the TCR alpha chain constant region (TRAC). In some embodiments, the TCR-cells have been modified to reduce functional tcrαβ signaling. The modification may be genomic, e.g., a gene editing that disrupts or knocks out at least a portion of the tcrα and/or tcrβ chains, thereby inactivating tcrαβ function, or epigenomic, e.g., using siRNA or other inhibitors to down-regulate or eliminate tcrαβ activity.
As used herein, the term "TCR knockdown" when used in reference to a population of cells produced using the methods provided in the present disclosure, means a population of cells comprising cells expressing endogenous tcrαβ heterodimers that is less than the population of cells harvested from a donor. For example, a population of TCR knockout cells (or TCR αβ -knockout cells) can comprise 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less than 1% of cells that express an endogenous TCR αβ complex.
Characterization of CAR T cells
Determination of cells of TCRαβ+ remaining in TCR-allogeneic CAR T products
The engineered allogeneic CAR-T product exemplifies the strategy to generate next generation CAR-T therapies. However, the potential risk of immune responses (such as GvHD) represents one of the important safety or efficacy issues for allogeneic CAR-T cell therapies. GvHD is produced by donor-derived T cells that recognize HLA mismatches by tcrαβ and have the potential to attack the patient's tissues. GvHD can be severe or even fatal even in HLA-matched donor environments, as slight mismatches can still elicit immune responses.
As described herein, the present disclosure provides methods for TCR-allogeneic CAR T cells that reduce or impair expression of a TCR αβ complex on the cell surface by introducing one or more genetic modifications to the TCR α chain or TCR β chain. Any tcrαβ+ cells are removed during tcrαβ+ cell rejection. Initially, engineered immune cells modified to be deficient in endogenous TCR a and/or TCR β genes are exposed to TCR-rejecting reagents. In some embodiments, the TCR depleting agent comprises an antibody that targets a TCR alpha polypeptide, a TCR beta polypeptide, or a TCR alpha beta heterodimer endogenously expressed on the surface of an immune cell.
anti-TCR antibodies or any other antibodies can be conjugated to biotin, for example, to facilitate further labeling and/or isolation using a secondary antibody (e.g., an anti-biotin antibody). The secondary antibody may be conjugated directly or indirectly with a magnetic knock-out reagent, such as magnetic microbeads (typically but not necessarily nanoparticles of about 50nm in diameter) or any other surface, such as agarose beads, sonic particles, plastic well plates, glass well plates, ceramic well plates, columns, cell culture bags or membranes. When magnetic microbeads are used, the microbeads aid in the separation of tcr+ cells from TCR-cells; when contacted with the magnetic column, the tcr+ cells can remain on the column, while unlabeled TCR-cells pass through the collection bag. The sonic particles may promote the separation of tcr+ from TCR-cells when exposed to sonic waves. Although anti-biotin antibodies are provided in the context of the disclosed methods, other biotin binding partners (such as streptavidin, avidin, and other biotin-recognizing proteins) may be employed in place of the anti-biotin antibodies in all of the methods provided herein.
In some embodiments, the provided cells may optionally be sorted for other cell surface markers. For example, a subset of the population of immune cells may comprise engineered immune cells that express an antigen-specific CAR that itself comprises one or more epitopes specific for one or more monoclonal antibodies (e.g., exemplary mimotope sequences; see, e.g., WO2016/120216, which is incorporated herein by reference). In some embodiments, the engineered immune cells expressing the CAR can optionally be sorted by using an anti-idiotype antibody that binds to an epitope present in the extracellular antigen binding domain of the CAR. The method comprises contacting a population of immune cells with a monoclonal antibody specific for the epitope, and selecting immune cells that bind to the monoclonal antibody to obtain a population of cells enriched for engineered immune cells expressing antigen-specific CARs.
In some embodiments, the monoclonal antibody specific for the epitope is optionally conjugated to a fluorophore. In this embodiment, the step of sorting or selecting cells that bind to the monoclonal antibody can be accomplished by Fluorescence Activated Cell Sorting (FACS).
In some embodiments, the monoclonal antibody specific for the epitope is optionally conjugated to a magnetic particle. In this embodiment, the step of sorting or selecting cells that bind to the monoclonal antibody can be accomplished by Magnetically Activated Cell Sorting (MACS).
In some embodiments of the disclosed methods, magnetic Activated Cell Sorting (MACS) can be used to effect sorting or isolation of tcr+ cells (optionally expressing CARs) from TCR-cells. Magnetically activated cell sorting is a method of separating various cell populations from cell surface antigens (CD molecules) by using superparamagnetic nanoparticles and columns. MACS can be used to obtain very pure cell populations. Cells in a single cell suspension may be magnetically labeled with microbeads. The sample is applied to a column composed of ferromagnetic material, which is covered with a coating that does not destroy the cells, allowing a rapid and gentle separation of the cells. Unlabeled cells will pass through the column while magnetically labeled cells remain in the column. The flow-through may be collected as an unlabeled cell fraction. After the washing step, the column is removed from the separator and the magnetically labeled cells are eluted from the column.
In some embodiments of the disclosed methods, sonic separation may be used instead of a magnetic-based separation method to achieve sorting or separation of tcr+ cells (optionally expressing CARs) from TCR-cells. While not wishing to be bound by theory, it is understood that sonic separation relies on three-dimensional standing waves to separate the components of the mixture. As disclosed below, in some embodiments, CAR T cells are also engineered to disrupt expression of CD52 to facilitate the lymphocyte depletion process. In the context of the disclosed methods, antibodies (such as anti-TCR antibodies and/or anti-CD 52 antibodies) can be conjugated to a surface, such as a sonic particle. The sonic particles may be beads. In one embodiment, the cells are exposed to an acoustic particle carrying one or more of an anti-TCR antibody and/or an anti-CD 52 antibody, thereby associating the acoustic particle with any cells expressing the target of interest. The cells are then placed in an acoustic chamber and exposed to acoustic waves. In view of the different properties of bead-associated cells and cells not labeled with antibody-bead particles, the sonic waves separate labeled and unlabeled cells, which can be collected while labeled cells (e.g., tcr+ or cd52+ cells) can be separated from unlabeled cells.
Current methods of removing residual tcr+ cells (tcrαβ+ cell knockout) (such as clinimmacs)And TCR kits), isolating tcr+ cells (tcrαβ+ cells) from TCR-cells (tcrαβ -cells) with anti-tcrαβ antibodies the anti-tcrαβ antibodies are used and can achieve a TCR-cell purity of 99% or greater in the final drug product (see, e.g., radestad et al, (2014) J Immunol Res, volume 2014: 578741). It is important to be able to confidently and reliably determine and quantify any remaining levels of tcr+ cells after final allogeneic CAR T drug depletion to understand any risk of GvHD associated with allogeneic CAR-T cell therapy, especially at high dose levels of use.
One of the challenges in accurately measuring the residual tcr+ levels is setting the appropriate cutoff/threshold (or gating) when analyzing the level of tcrαβ, for example, by flow cytometry. Allogeneic T cells from different donors may have different baseline levels of surface tcrαβ expression when measured by a given method. It is therefore difficult to determine a universal cutoff or threshold for tcrαβ positivity for all donor T cells: setting a cutoff value or threshold that is too high may result in insufficient reporting of the tcrαβ+ event and an increased potential risk to the patient; setting a cutoff value or threshold that is too low can result in excessive reporting of TCR αβ+ events and depletion of TCR-allogeneic CAR T cells suitable for clinical research or commercial use. To account for the differences, unmodified T cells or source cells (such as PBMCs from each donor) would have to be retained and stored for subsequent use in the gating settings. Storage and transportation can be complex and the process cumbersome, especially in a large scale manufacturing environment, different batches of CAR T cell products can be produced from different donors.
Furthermore, the lack of compatible detection reagents can complicate the problem. TCR αβ knockout and post-knockout TCR αβ detection using the same antibodies can result in inaccurate measurement and reporting of the remaining TCR αβ+ cells.
Thus, in one aspect, the present disclosure provides a method of analyzing a genetically modified allogeneic CAR T drug, e.g., by measuring or determining any remaining tcrαβ+ T cells present in the drug, wherein the method does not require a donor-matched cutoff value or threshold for baseline levels of tcrαβ expression above which tcrαβ is considered positive. In some embodiments, the determination of the percentage or number of TCR αβ+ T cells remaining does not require the use of a predetermined cutoff value or threshold value and/or detection reagents that are compatible with TCR αβ rejection reagents. In some embodiments, the percentage or number of TCR αβ+ cells remaining can be determined using an internal biological control. In some embodiments, the percentage or number of tcrαβ+ cells remaining can be determined by calculating the T cells of cd3+/tcrγδ+, wherein the T cells are identified based on the surface expression of CD 5.
Thus, in another aspect, the present disclosure provides a method of detecting T cells by detecting surface expression of CD 5. In some embodiments, the T cells do not express a surface TCR comprising tcrαβ and/or tcrγδ, and therefore do not express or express very low levels of surface CD3. In some embodiments, the methods provide for quantitative measurement of T cells that do not express a surface TCR comprising tcrαβ and/or tcrγδ, and thus do not express or express very low levels of surface CD3. In some embodiments, the method further comprises detecting surface expression of cd45+. In some embodiments, the T cell is a genetically modified T cell.
Flow cytometry can be used to quantify cells expressing a particular surface marker (such as tcrαβ), or to quantify cells of a particular cell type in a population of cells. In general, flow cytometry is a method of quantifying components or structural features of cells, mainly by optical means. Since different cell types can be distinguished by quantifying structural features, flow cytometry and cell sorting can be used to count and sort cells of different phenotypes in a mixture.
Flow cytometric analysis involves two main steps: 1) Labeling selected cell types with one or more detectable markers, and 2) determining the ratio of the number of labeled cells relative to the total number of cells in the population. In some embodiments, the method of labeling a cell type comprises binding the labeled antibody to a marker expressed by a particular cell type. The antibody may be directly labeled with a fluorescent compound or indirectly labeled with a second antibody that recognizes the fluorescent label of the first antibody, for example.
In some embodiments, the provided cells can be further analyzed for expression of the CAR on the surface. The presence of a CAR can be detected by using an anti-idiotype antibody specific for the antigen binding domain of the CAR. In some embodiments, the presence of the CAR can be detected by using antibodies specific for other portions of the CAR. In some embodiments, the presence of a CAR can be detected using an antigen that is specifically recognized and bound by the antigen binding domain of the CAR. In some embodiments, the antigen is labeled directly or indirectly to facilitate detection. In some embodiments, the CAR can be detected by extracellular or intracellular staining.
In some embodiments, the cells are analyzed for other surface markers to indicate different cell types in the cell population, e.g., effector cells, effector memory cells, central memory cells, stem central memory cells, etc., based on the widely accepted specific surface markers for each cell type. In another aspect, provided herein are methods of detecting surface markers indicative of other properties of a CAR T cell product.
In some embodiments, the provided cells can be further analyzed for other surface markers. In some embodiments, the cells are subjected to an analysis of surface markers, the presence or absence of which may reflect the genetic modification of the cells. For example, cells are genetically modified to knock out TCR as well as CD52 genes, thereby obtaining resistance to anti-CD 52 antibodies. In some embodiments, the anti-CD 52 antibody is used as part of a lymphocyte depletion strategy as described below. Analysis of surface CD52 levels reflects gene knockout events in the CD52 locus of the cell. In some embodiments, the cells are subjected to analysis of other surface markers, the levels of which may be indicative of the efficacy or function of the cells. The analysis may be qualitative or quantitative.
Determination of potency and/or multifunctional CAR T cells
In this further aspect, the present disclosure provides a method for analyzing and/or determining the efficacy and/or versatility of an immune cell. In some embodiments, the immune cell is an engineered immune cell, e.g., a CAR T cell. Currently, methods for assessing the efficacy of CAR T products are quite limited. Upon exposure/binding to target cells, CAR T cells exert cytotoxicity in part by secreting one or more effector cytokines. Effective cytokine induction can be used as an indicator of the efficacy or versatility of CAR T cells. Secreted cytokines can be measured by an immunoassay, such as ELISA. Cytokine induction of CAR T cells can also be assessed by intracellular staining following fixation of the cells. However, both of these methods are cumbersome and neither method is suitable for a highly simplified GMP preparation process.
As used herein, efficacy can refer to the ability of one or more immune cells (such as CAR T cells) to kill target cells (such as antigen positive tumor cells).
As used herein, versatility can refer to the ability of one or more immune cells (such as CAR T cells) to separate more than one effector cytokine or molecule upon activation of a target or antigen. In some embodiments, the multifunctional CAR T cell secretes two or more effector cytokines, or three or more effector cytokines upon activation of the target or antigen.
CD107, including CD107a (or lysosomal associated membrane protein (LAMP 1)) and CD107b (LAMP 2), are the major lysosomal membrane glycoproteins. The functions of CD107a and CD107b overlap to a large extent. CD107 is released to the cell surface upon T cell activation and has been used as a T cell degranulation marker. T cell activation can also be measured by assessing elevated levels of effector cytokines alone (such as tnfα, IL2, GM-CSF, ifnγ, etc.), by intracellular staining. See, e.g., priceman et al, 2018, oncominium, 7:e1380764; and Kochenderfer et al, 2015,J.Clinical Oncology,33:540. The intracellular staining step of these effector cytokines is not easily adaptable to GMP manufacturing processes. The data provided by the present disclosure indicate that CD107a surface expression is associated with induction of one or more, two or more, three or more effector cytokines upon antigen activation. This correlation has not previously been shown in autologous or allogeneic CAR T cells (including TCR-allogeneic CAR T cells).
Thus, in this aspect, the present disclosure provides a method of detecting an increase in the surface expression level of CD107 of a CAR T cell upon exposure of the CAR T cell to an antigen or a target cell, wherein an increase in the level of CD107 compared to the level prior to antigen activation can be used as a representation or indicator of the efficacy or versatility of the CAR T cell. In some embodiments, an increase in surface CD107 expression is indicative of induction of one or more, two or more, or three or more effector cytokines, wherein the effector cytokines are INFγ, TNF α, IL2, GM-CSF, CXCL1, IL-1B, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-17, IL-21, IL-22, IL-23, CXCL11, mic 1a, mic 1B, mic 3a, TNFb, perforin, granzyme A, granzyme B, granzyme H, CCL, IP-10, CCL5, TGF β, sCD137, sCD40L, MCP-1, and/or MCP-4. In some embodiments, the effector cytokines are tnfα and ifnγ. In some embodiments, the effector cytokines are tnfα and IL2. In some embodiments, the effector cytokines are ifnγ and IL2. In some embodiments, the effector cytokines are tnfα, ifnγ, and IL2. The correlation between CD107a and ifnγ induction is strongest, and it is a key cytokine for eradicating tumor cells in the tumor microenvironment. In some embodiments, the present disclosure provides a method of detecting an increase in surface CD107 expression of CAR T cells upon antigen activation, wherein the increased level of CD107 as compared to the level prior to antigen activation defines target-specific induction of two or more of ifnγ, IL2, and/or tnfα in all car+ immune subpopulations. In some embodiments, the increase in the level of CD107 is at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold greater than the level prior to antigen activation.
In some embodiments, the CAR T cell is an autologous CAR T cell. In some embodiments, the CAR T cells are allogeneic CAR T cells.
In some embodiments, the CAR T cells are TCR-allogeneic CAR T cells. In contrast to tcr+car T cells, in the absence of a functional TCR, activation of engineered T cells depends on the interaction of the CAR with the antigen. The correlation of the elevation of surface CD107 with induction of effector cytokines was not shown in CAR T cells in the absence of a functional tcrαβ complex. In some embodiments, the present disclosure provides methods of detecting an increase in surface CD107, the increase in surface CD107 being an indicator of the efficacy and/or versatility of TCR-negative allogeneic CAR T cells.
The methods of determining potency or versatility provided herein can be used for quality control of CAR T cells in a manufacturing process. In some embodiments, the present disclosure provides a method of preparing an engineered immune cell (such as a CAR T cell), the method comprising the steps of: generating an engineered immune cell, measuring an increase in surface CD107 levels of the engineered immune cell after antigen activation of the engineered immune cell drug substance, and if the increase in surface CD107 levels reaches a threshold, filling the drug substance into a container or vial to produce the drug substance. In some embodiments, if the surface CD107 level does not meet the threshold, the downstream loading step is stopped. In some embodiments, the threshold is a predetermined threshold. In some embodiments, the engineered immune cell is an allogeneic CAR T cell. In some embodiments, the allogeneic CAR T cells are TCR-allogeneic CAR T cells. In some embodiments, the predetermined threshold is raised by at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, or at least 10-fold from the level prior to antigen activation.
Measuring surface CD107 expression by, for example, flow cytometry can be incorporated into the manufacturing quality control process more easily than measuring effector cytokines alone in cells. In some embodiments, the methods of detecting surface CD107 after antigen activation provided herein do not require a step of measuring one or more effector cytokines. In further embodiments, the method of analyzing the efficacy and/or versatility of an engineered immune cell (such as a CAR T cell) by detecting surface CD107 after antigen activation does not require a step of measuring one or more effector cytokines.
The methods provided herein can also be applied to analyze samples from patients receiving cell therapies (such as CAR T cell therapies). In some embodiments, the sample is a peripheral blood sample from the patient, wherein an elevated level of surface CD107 of the CAR T cells after antigen activation is indicative of efficacy or versatility of the CAR T cell therapy. In some embodiments, the method further comprises the step of detecting the presence of CAR T cells in the sample. In some embodiments, the determination of surface CD107 after antigen activation may assist the physician in making dosing or treatment decisions.
Accordingly, the present disclosure provides a method for measuring CD107 on the surface of a CAR T cell after antigen stimulation, wherein an increase in the level of surface CD107 after antigen stimulation compared to the level of surface CD107 prior to antigen stimulation is indicative of a multi-functional CAR T cell. In some embodiments, the multifunctional CAR T cells express increased levels of one or more, or two or more effector cytokines. In some embodiments, the multifunctional CAR T cells express increased levels of two or more effector cytokines.
Antigen stimulation (or antigen activation) of CAR T cells can be achieved, for example, by binding to an antigen, binding to a target cell (e.g., a target tumor cell that expresses an antigen), or by co-culturing with a target cell (e.g., a target tumor cell that expresses an antigen). In some embodiments, the surface CD107 of the CAR T cells is measured about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours after antigen activation. In some embodiments, the surface CD107 of the CAR T cells is measured about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours after co-culturing with the target cells. In some embodiments, the surface CD107 of the CAR T cells is measured about 6 hours after co-culturing with the target cells. In some embodiments, the CAR T cell is an autologous CAR T cell. In some embodiments, the CAR T cells are allogeneic CAR T cells. In some embodiments, the CAR T cells are TCR-allogeneic CAR T cells. In some embodiments, CD107 is CD107a (e.g., genBank accession No. nm_005561 or NCBI gene id#3916) and/or CD107b (e.g., genBank accession No. nm_001122606 or NCBI gene id#3920). In some embodiments, the CAR T cells are prepared in accordance with cGMP. In some embodiments, the one or more effector cytokines are INFg, TNFa, IL, GM-CSF, CXCL1, IL-1B, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-17, IL-21, IL-22, IL-23, CXCL11, mip1a, mip1B, mip3a, TNFb, perforin, granzyme A, granzyme B, granzyme H, CCL, IP-10, CCL5, TGFb, sCD137, sCD40L, MCP-1, and/or MCP-4.
The present disclosure also provides an overall process for characterizing and analyzing CAR T (particularly TCR-allogeneic CAR T drugs). Accordingly, in one aspect, the present disclosure provides a method for analyzing an engineered immune cell population, e.g., TCR-allogeneic CAR T cells, the method comprising the steps of: the percentage or number of tcrαβ+ T cells in the immune cell population is measured or determined, and the level of surface CD107 in the immune cell population after antigen stimulation is measured.
In some embodiments, the present disclosure provides a method of analyzing an immune cell population, wherein the immune cell population has been engineered to introduce one or more genetic modifications at a TCR a and/or TCR β locus that reduce or impair TCR a surface expression, and wherein the lymphocyte population has been engineered to express a Chimeric Antigen Receptor (CAR), the method comprising the steps of: (a) Obtaining or measuring viable cd45+ cells from the population of immune cells; (b) Obtaining or measuring cd5+/cd3+ cells from the cells described in step a); (c) Measuring or determining the percentage or number of cd3+/tcrγδ -cells from the cells described in step (b), wherein the percentage or number of cd3+/tcrγδ -cells described in step (c) represents the percentage or number of tcrαβ+ T cells in the immune cell population; and (d) measuring the percentage or number of (i) car+ T cells in the population of immune cells; and/or (ii) the level of surface CD107 following antigen stimulation. In some embodiments, the workflow of the method may be as shown in fig. 3.
In some embodiments, the method further comprises the step of measuring the percentage or number of car+ T cells. In some embodiments, the percentage or number of car+ T cells can be determined by using an agent (e.g., an anti-idiotype antibody or antigen). The antigen may be soluble or immobilized on a solid surface. The reagent may be directly labeled for detection or bound by a secondary labeled reagent for detection. In some embodiments, the method further comprises the step of measuring or detecting cd52+ cells. In some embodiments, the CAR T cells are prepared during GMP preparation. In some embodiments, the engineered immune cell population is TCR-allogeneic CAR T cells prepared during GMP preparation. In some embodiments, the engineered immune cell population is a GMP allogeneic CAR T drug substance or drug.
In certain embodiments, the CAR T cell has specificity for egfrvlll, WT-1, CD20, CD23, CD30, CD38, CD33, CD133, MHC-WT1, TSPAN10, MHC-PRAME, liv1, ADAM10, chra 2, leY, NKGD2D, CS1, CD44v6, ROR1, tight junction protein (Claudin) -18.2, muc17, fapα, ly6G6D, c6orf23, G6D, MEGT1, NG25, CD19, BCMA, FLT3, CD70, DLL3, CD52, or CD 34. In certain embodiments, the CAR T cell is an egfrvlll CAR T cell, a CD19 CAR T cell, a CD20 CAR T cell, a CD33 CAR T cell, a ROR1 CAR T cell, a CD70 CAR T cell, a FLT3 CAR T cell, a BCMA CAR T cell, or a DLL3 CAR T cell. In certain embodiments, the CAR T cell is a CD19 CAR T cell. In certain embodiments, the CD19 CAR T cell comprises a C19 CAR comprising the sequence set forth in SEQ ID NO. 1 or SEQ ID NO. 2.
EVQLQQSGPELIKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYINPYNDGTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARGTYYYGSRVFDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQAAPSIPVTPGESVSISCRSSKSLLNSNGNTYLYWFLQRPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPFTFGAGTKLELKRSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:1)
METDTLLLWVLLLWVPGSTGEVQLQQSGPELIKPGASVKMSCKASGYTFTSYVMHWVKQKPGQGLEWIGYINPYNDGTKYNEKFKGKATLTSDKSSSTAYMELSSLTSEDSAVYYCARGTYYYGSRVFDYWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQAAPSIPVTPGESVSISCRSSKSLLNSNGNTYLYWFLQRPGQSPQLLIYRMSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPFTFGAGTKLELKRSDPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR(SEQ ID NO:2)
1. Immune cells
Cells suitable for use in the methods and/or reagents described herein include immune cells.
Cells (e.g., immune cells) for use in the methods described herein can be obtained from a subject prior to in vitro manipulation or genetic modification (e.g., as described herein). Cells may be obtained from a number of non-limiting sources including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, stem cells or iPSC-derived immune cells, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In some embodiments, any number of T cell lines available and known to those of skill in the art may be used. In some embodiments, the cells may be derived from healthy donors, from patients diagnosed with cancer, or from patients diagnosed with infection. In some embodiments, the cells may be part of a mixed population of cells exhibiting different phenotypic characteristics.
In some embodiments, the immune cells are autoimmune cells obtained from a subject that will ultimately receive the engineered immune cells. In some embodiments, the immune cells are allogeneic immune cells obtained from a donor, which is a different individual than the subject to which the engineered immune cells are to be received.
In some embodiments, the immune cells comprise T cells. T cells may be obtained from a variety of sources including Peripheral Blood Mononuclear Cells (PBMCs), bone marrow, lymph node tissue, cord blood, thymus tissue, stem cells or iPSC-derived T cells, tissue from the site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments, any number of techniques known to the skilled artisan may be used, such as FICOLL TM T cells are isolated from a blood volume collected from a subject.
Cells may be obtained from circulating blood of an individual by apheresis. Apheresis products typically contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated leukocytes, erythrocytes, and platelets. In certain embodiments, cells collected by apheresis may be washed to remove plasma components and placed in an appropriate buffer or medium for subsequent processing.
PBMCs may be used directly for genetic modification of immune cells (such as CARs or TCRs) using methods as described herein. In certain embodiments, after isolation of PBMCs, T lymphocytes may be further isolated, and cytotoxic and helper T lymphocytes may be sorted into subpopulations of naive, memory and effector T cells before or after genetic modification and/or expansion.
In certain embodiments, for example, using a PERCOL TM Gradient centrifugation separates T cells from PBMCs by lysing erythrocytes and rejecting monocytes. Specific subsets of T cells (such as ccr7+, cd95+, cd122, cd27+, cd69+, cd127+, cd28+, cd3+, cd4+, cd8+, cd25+, cd62l+, cd45ra+ and cd45ro+ T cells) can be further isolated by positive or negative selection techniques known in the art. For example, enrichment of a T cell population by negative selection can be achieved with a combination of antibodies directed against surface markers unique to the cells selected negatively. One of the methods used herein is cell sorting and/or selection by negative magnetic immunoadhesion or flow cytometry using a mixture of monoclonal antibodies directed against cell surface markers present on negatively selected cells. For example, to enrich for cd4+ cells by negative selection, monoclonal antibody mixtures typically include antibodies to CD14, CD20, CD11b, CD16, HLA-DR, and CD 8. Flow cytometry and cell sorting may also be used to isolate a population of cells of interest for use in the present disclosure.
In some embodiments, the T cell population is enriched for cd4+ cells.
In some embodiments, the T cell population is enriched for cd8+ cells.
In some embodiments, cd8+ cells are further sorted into primordial, central memory, and effector cells by identifying cell surface antigens associated with each of these cell types. In some embodiments, expression of phenotypic markers for primary T cells includes cd45ra+, CD95-, il2rβ -, ccr7+, and cd62l+. In some embodiments, expression of a phenotypic marker of a stem cell memory T cell includes cd45ra+, cd95+, il2rβ+, ccr7+, and cd62l+. In some embodiments, expression of a phenotypic marker of central memory T cells includes cd45ro+, cd95+, il2rβ+, ccr7+, and cd62l+. In some embodiments, the expression of a phenotypic marker for effector memory T cells includes CD45RO+, CD95+, IL2Rβ+, CCR 7-and CD62L-. In some embodiments, expression of a phenotypic marker of T effector cells includes CD45RA+, CD95+, IL2Rβ+, CCR 7-and CD62L-. Thus, cd4+ and/or cd8+ T helper cells can be sorted into primordial, stem cell memory, central memory, effector memory, and T effector cells by identifying a population of cells with cell surface antigens.
It will be appreciated that PBMCs may also include other cytotoxic lymphocytes, such as NK cells or NKT cells. Expression vectors carrying coding sequences for chimeric receptors as disclosed herein can be introduced into a population of human donor T cells, NK cells, or NKT cells. Standard procedures are used to cryopreserve CAR-expressing T cells for storage and/or preparation for use in human subjects. In one embodiment, in vitro transduction, culture, and/or expansion of T cells is performed in the absence of non-human animal derived products, such as fetal calf serum (fetal calf serum/fetal bovine serum). In various embodiments, the cryopreservation medium may include, for exampleCS2, CS5 or CS10 or other medium containing DMSO, or medium without DMSO.
2. Engineered immune cells
Provided herein are engineered immune cells (e.g., CAR-T cells) that express a CAR of the present disclosure.
In some embodiments, the engineered immune cells comprise a population of CARs, each CAR comprising an extracellular antigen binding domain. In some embodiments, the engineered immune cells comprise a population of CARs, each CAR comprising a different extracellular antigen binding domain. In some embodiments, the immune cells comprise a population of CARs, each CAR comprising the same extracellular antigen-binding domain.
The engineered immune cells may be allogeneic or autologous.
In some embodiments, the engineered immune cell is a T cell (e.g., an inflammatory T lymphocyte cytotoxic T lymphocyte, regulatory T lymphocyte, helper T lymphocyte, tumor Infiltrating Lymphocyte (TIL)), NK cell, NK-T cell, TCR expressing cell, dendritic cell, killer dendritic cell, mast cell, or B cell. In some embodiments, the cells may be derived from the group consisting of cd4+ T lymphocytes and cd8+ T lymphocytes. In some exemplary embodiments, the engineered immune cell is a T cell. In some exemplary embodiments, the engineered immune cells are αβ T cells. In some exemplary embodiments, the engineered immune cell is a γδ T cell. In some exemplary embodiments, the engineered immune cell is a macrophage.
In some embodiments, the engineered immune cells may be derived from, for example, but not limited to, stem cells. The stem cells may be adult stem cells, non-human embryonic stem cells, more specifically non-human stem cells, umbilical cord blood stem cells, progenitor cells, bone marrow stem cells, induced pluripotent stem cells (ipscs), totipotent stem cells, or hematopoietic stem cells. The stem cells may be CD34+ or CD34-.
In some embodiments, the cells are obtained from or prepared from peripheral blood. In some embodiments, the cells are obtained from or prepared from Peripheral Blood Mononuclear Cells (PBMCs). In some embodiments, the cells are obtained from or prepared from bone marrow. In some embodiments, the cells are obtained from or prepared from cord blood. In some embodiments, the cell is a human cell. In some embodiments, the cell is transfected or transduced with a nucleic acid vector using a method selected from the group consisting of: electroporation, sonoporation, biolistics (e.g., gene gun), transfection, lipofection, polymeric transfection, nanoparticle, viral transduction or viral transfection (e.g., retrovirus, lentivirus, AAV) or polyplex. In some embodiments, the cell is a T cell that has been reprogrammed from a non-T cell. In some embodiments, the cell is a T cell that has been reprogrammed from a T cell.
Binding agents (including antibodies and fragments thereof)
In embodiments, the disclosed methods include the use of antibodies or antigen binding agents (e.g., comprising an antigen binding domain or comprising an antibody or fragment thereof). As discussed below, in various embodiments, the engineered immune cells may additionally comprise a binding agent.
As used herein, the term "antibody" refers to a polypeptide comprising canonical immunoglobulin sequence elements sufficient to confer specific binding to a particular target antigen. As known in the art, an intact antibody produced in nature is an approximately 150kD tetrameric reagent consisting of two identical heavy chain polypeptides (about 50kD each) and two identical light chain polypeptides (about 25kD each) that associate with each other into a structure commonly referred to as a "Y-shape". Each heavy chain consists of at least four domains (each of about 110 amino acids in length) -these four domains are amino-terminal Variable (VH) domains (positioned at the end of the Y structure), followed by three constant domains: CHI, CH2 and carboxy-terminal CH3 (located at the base of the stem of Y). The short region is referred to as a "switch" and connects the heavy chain variable region to the constant region. The "hinge" links the CH2 and CH3 domains to the rest of the antibody. Two disulfide bonds in the hinge region link the two heavy chain polypeptides in the intact antibody to each other. Each light chain consists of two domains-the amino-terminal Variable (VL) domain followed by the carboxy-terminal Constant (CL) domain. Those skilled in the art are well familiar with antibody structures and sequence elements, recognize the "variable" and "constant" regions in the provided sequences, and understand that there may be some flexibility in defining "boundaries" between these domains, such that different presentations of the same antibody chain sequence may, for example, represent that such boundaries at a position are offset by one or a few residues relative to different presentations of the same antibody chain sequence.
The intact antibody tetramer is composed of two heavy chain-light chain dimers, wherein the heavy and light chains are linked to each other by a single disulfide bond; the other two disulfide bonds connect the heavy chain hinge regions to each other, thereby connecting the dimers to each other and forming a tetramer. Naturally occurring antibodies are also glycosylated, typically on the CH2 domain. Each domain in a natural antibody has a structure characterized by an "immunoglobulin fold" formed by the stacking of two beta sheets (e.g., 3, 4, or 5 strand folds) together in a compressed antiparallel beta barrel. Each variable domain contains three hypervariable loops called "complement determining regions" (CDR 1, CDR2, and CDR 3) and four slightly invariant "framework" regions (FR 1, FR2, FR3, and FR 4). When the natural antibody is folded, the FR regions form a β -sheet that the domains provide the structural framework, and the CDR loop regions of the heavy and light chains are clustered together in three dimensions, creating a single hypervariable antigen binding site located at the end of the Y structure. The Fc region of naturally occurring antibodies binds to elements of the complement system and also to receptors on effector cells, including, for example, effector cells that mediate cytotoxicity. As is known in the art, the affinity and/or other binding properties of the Fc region for Fc receptors can be modulated by glycosylation or other modifications. In some embodiments, antibodies produced and/or employed according to the present invention include glycosylated Fc domains, including those having modified or engineered such glycosylated Fc domains.
For the purposes of this disclosure, in certain embodiments, any polypeptide or polypeptide complex that comprises sufficient immunoglobulin domain sequence present in a native antibody may be referred to and/or used as an "antibody," whether such polypeptide is naturally-occurring (e.g., produced by the reaction of an organism with an antigen), or produced by recombinant engineering, chemical synthesis, or other artificial systems or methods. In some embodiments, the antibody is polyclonal; in some embodiments, the antibody is monoclonal. In some embodiments, the antibody has a constant region sequence that is characteristic of a mouse, rabbit, primate, or human antibody. In some embodiments, the antibody sequence elements are humanized, primate, chimeric, etc., as is known in the art.
Furthermore, as used herein, the term "antibody" may refer to any of the constructs or forms known or developed in the art for utilizing antibody structural and functional features in alternative presentation. For example, in some embodiments, the form of the antibody employed in the methods of the present disclosure is selected from, but is not limited to: intact IgA, igG, igE or IgM antibodies; bispecific or multispecific antibodies (e.g., Etc.); antibody fragments, such as Fab fragments, F (ab) 2 fragments, fd fragments, and isolated CDRs, or a collection thereof; single-chain variable fragments (scFV); polypeptide-Fc fusions; single domain antibodies (e.g., shark single domain antibodies, such as IgNAR or fragments thereof); camelid antibodies (also referred to herein as nanobodies or VHHs); shark antibodies, masking antibodies (e.g.)>) The method comprises the steps of carrying out a first treatment on the surface of the Small Modular Immunopharmaceuticals (SMIPs) TM ) The method comprises the steps of carrying out a first treatment on the surface of the Single-chain or tandem diabodies>VHH;/>A minibody; />Ankyrin repeat protein or->DART; TCR-like antibodies;a micro protein;and->In some embodiments, the antibody may lack covalent modifications (e.g., linkages of glycans) that are naturally occurring. In some embodiments, the antibodies can contain covalent modifications (e.g., attachment of glycans), payloads (e.g., detectable moieties, therapeutic moieties, catalytic moieties, etc.), or other pendant groups (e.g., polyethylene glycol, etc.).
As used herein, the term "antibody reagent" generally refers to a reagent that specifically binds to a particular antigen. In some embodiments, the term encompasses any polypeptide or polypeptide complex comprising an immunoglobulin structural element sufficient to confer specific binding. Exemplary antibody reagents include, but are not limited to, monoclonal antibodies or polyclonal antibodies. In some embodiments, the antibody agent may comprise one or more constant region sequences that are characteristic of a mouse, rabbit, primate, or human antibody. In some embodiments, the antibody agent may comprise one or more sequence elements that are humanized, primate-derived, chimeric, etc., as is known in the art. In various embodiments, the term "antibody reagent" is used to refer to one or more of constructs or forms known or developed in the art for exploiting antibody structural and functional characteristics in alternative presentation. For example, the form of antibody reagent employed in accordance with the present invention is selected from, but is not limited to: intact IgA, igG, igE or IgM antibodies; bispecific or multispecific antibodies (e.g., Etc.); antibody fragments such as Fab fragments, fab 'fragments, F (ab') 2 fragments, fd fragments and isolated CDRs or a collection thereof; a single chain Fv; polypeptide-Fc fusions; single domain antibodies (e.g., shark single domain antibodies, such as IgNAR or fragments thereof); camel antibodies; masking antibodies (e.g.)>) The method comprises the steps of carrying out a first treatment on the surface of the Small Modular Immunopharmaceuticals (SMIPs) TM ) The method comprises the steps of carrying out a first treatment on the surface of the Single-chain or tandem diabodies>VHH;/> A minibody; />Ankyrin repeat protein or->DART; TCR-like antibodies; a micro protein;and->
Antibodies or antibody reagents useful in performing the methods of the present disclosure may be single-stranded or double-stranded. In some embodiments, the antibody or antigen binding molecule is single-chain. In certain embodiments, the antigen binding molecule is selected from the group consisting of: scFv, fab, fab ', fv, F (ab') 2 A dAb, and any combination thereof.
Antibodies and antibody reagents include antibody fragments. An antibody fragment comprises a portion of an intact antibody, such as an antigen binding or variable region of an intact antibody. Antibody fragments include, but are not limited to, fab '-SH, F (ab') 2 Fv, diabodies, linear antibodies, multispecific antibodies formed from antibody fragment antibodies and scFv fragments, and other fragments. Antibodies also include, but are not limited to, polyclonal, monoclonal, chimeric dAbs (domain antibodies), single chain, fab, fa, F (ab') 2 Fragments and scFv. The antibody may be a complete antibody, or an immunoglobulin, or an antibody fragment. Antibody fragments can be prepared by a variety of techniques including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells, e.g., E.coli, chinese Hamster Ovary (CHO) cells, or phage, as known in the art.
In some embodiments, the antibody or antibody reagent may be a chimeric antibody (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al, proc. Natl. Acad. Sci. USA,81:6851-6855 (1984)). Chimeric antibodies may be antibodies in which a portion of the heavy and/or light chains are derived from a particular source or species, while the remainder of the heavy and/or light chains are derived from a different source or species. In one example, a chimeric antibody may comprise a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate (such as a monkey)) and a human constant region. In another example, the chimeric antibody may be a "class switch" antibody, wherein the class or subclass has been altered from the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
In some embodiments, the chimeric antibody may be a humanized antibody (see, e.g., almagro and Franson, front. Biosci.,13:1619-1633 (2008); riechmann et al, nature,332:323-329 (1988); queen et al, proc. Natl Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos. 5,821,337, 7,527,791, 6,982,321 and 7,087,409; kashmiri et al, methods 36:25-34 (2005); padlan, mol. Immunol,28:489-498 (1991); dall' Acqua et al, methods,36:43-60 (2005); osbourn et al, methods,36:61-68 (2005); and Klimka et al, br. J. Cancer, 83:252-260). Humanized antibodies are chimeric antibodies comprising amino acid residues from a non-human hypervariable region and amino acid residues from a human FR. In certain embodiments, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable regions (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of the Framework Regions (FR) correspond to those of a human antibody. The humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody.
In some embodiments, the antibodies or antibody reagents provided herein are human antibodies. Human antibodies can be produced using a variety of techniques known in the art (see, e.g., van Dijk and van de Winkel, curr. Opin. Pharmacol,5:368-74 (2001); and Lonberg, curr. Opin. Immunol,20:450-459 (2008)). A human antibody may be an antibody whose amino acid sequence corresponds to that produced by a human or human cell or derived from an antibody of non-human origin that utilizes human antibody lineages or other human antibody coding sequences. The definition of such human antibodies expressly excludes humanized antibodies comprising non-human antigen binding residues. Human antibodies can be prepared using methods well known in the art.
Chimeric antigen receptor
As used herein, a Chimeric Antigen Receptor (CAR) is a protein that specifically recognizes a target antigen (e.g., a target antigen on a cancer cell). When bound to a target antigen, the CAR can activate immune cells to attack and destroy cells (e.g., cancer cells) that carry the antigen. CARs may also incorporate co-stimulatory or signaling domains to increase their potency. See Krause et al, journal of experimental medicine, volume 188, no. 4, 1998 (619-626); finney et al, journal of immunology (Journal of Immunology), 1998,161:2791-2797, song et al, blood (2012), 119:696-706; kalos et al, science/conversion medicine (Sci. Transl. Med.) 3:95 (2011); porter et al, new England journal of medicine (N.Engl. J.Med.)) 365:725-33 (2011), and Gross et al, annual reviews of pharmacology and toxicology (Annu. Rev. Pharmacol. Toxicol.)) 56:59-83 (2016); U.S. patent nos. 7,741,465 and 6,319,494.
The chimeric antigen receptors described herein comprise an extracellular domain, a transmembrane domain, and an intracellular domain, wherein the extracellular domain comprises an antigen binding domain that specifically binds to a target.
In some embodiments, the antigen-specific CAR further comprises a safety switch and/or one or more monoclonal antibody-specific epitopes.
i. Antigen binding domains
As discussed above, the CARs described herein comprise an antigen binding domain. As used herein, "antigen binding domain" means any polypeptide that binds to a specified target antigen. In some embodiments, the antigen binding domain binds to an antigen on a tumor cell. In some embodiments, the antigen binding domain binds to an antigen on a cell involved in a hyperproliferative disease.
In some embodiments, the antigen binding domain comprises a variable heavy chain, a variable light chain, and/or one or more CDRs as described herein. In some embodiments, the antigen binding domain is a single chain variable fragment (scFv) comprising a light chain CDR (CDR 1, CDR2, and CDR 3) and a heavy chain CDR (CDR 1, CDR2, and CDR 3).
An antigen binding domain is said to be "selective" when it binds to one target more tightly or with a higher affinity than to a second target.
The antigen binding domain of the CAR selectively targets a cancer antigen. In some embodiments, the cancer antigen is selected from egfrvlll, WT-1, CD20, CD23, CD30, CD38, CD33, CD133, MHC-WT1, TSPAN10, MHC-PRAME, liv1, ADAM10, chra 2, leY, NKGD2D, CS1, CD44v6, ROR1, tight junction protein (Claudin) -18.2, muc17, fapα, ly6G6D, c6orf23, G6D, MEGT1, NG25, CD19, BCMA, FLT3, CD70, DLL3, CD52, or CD34. In some embodiments, the CAR comprises an antigen binding domain that targets egfrvlll, WT-1, CD20, CD23, CD30, CD38, CD33, CD133, MHC-WT1, TSPAN10, MHC-PRAME, liv1, ADAM10, chra 2, leY, NKGD2D, CS1, CD44v6, ROR1, tight junction protein (Claudin) -18.2, muc17, fapα, ly6G6D, c orf23, G6D, MEGT1, NG25, CD19, BCMA, FLT3, CD70, DLL3, CD52, or CD34.
In some embodiments, the cancer antigen is selected from the group consisting of: carbonic Anhydrase IX (CAIX), carcinoembryonic antigen (CEA), CDS, CD7, CDIO, CD19, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD49f, CD56, CD74, CD123, CD133, CD138, cytomegalovirus (CMV) infected cell antigen (e.g., cell surface antigen), epithelial glycoprotein (EGP 2), epithelial glycoprotein-40 (EGP-40), epithelial cell adhesion molecule (EpCAM), receptor tyrosine protein kinase erb-B2,3,4, folate Binding Protein (FBP), fetal acetylcholine receptor (AChR), folate receptor, ganglioside G2 (GD 2), ganglioside G3 (GD 3), human epidermal growth factor receptor 2 (HER-2), human telomerase reverse transcriptase (hT), interleukin-13 receptor subunit alpha-2 (IL-13 Ra 2), kappa-light chain, kinase insertion domain receptor (KDR), lewis A (CA 19.9), cell adhesion molecule (LIGE), human tumor cell adhesion antigen (NCE-16), human tumor cell adhesion antigen (PSLI-1), human tumor cell adhesion antigen (PSC-2), human tumor antigen (PSOIL-2), human tumor cell adhesion antigen (PSE-1, PSO5, PSOIL-2), human tumor antigen (PSO1, PSO5, human tumor antigen (PSO1, human tumor antigen (PSOG2), human tumor antigen (PSR), human tumor antigen (PSP), human tumor antigen (3), human tumor antigen (human tumor antigen), human antigen (human tumor antigen (human 2), and human tumor antigen (human tumor antigen) Vascular endothelial growth factor R2 (VEGF-R2) and Wilms' tumor protein (WT-1).
Variants of antigen binding domains (e.g., variants of CDRs, VH and/or VL) are also within the scope of the disclosure, e.g., variable light chains and/or variable heavy chains, each having at least 70% -80%, 80% -85%, 85% -90%, 90% -95%, 95% -97%, 97% -99% or greater than 99% identity to the amino acid sequence of the antigen binding domain sequence. In some cases, such molecules include at least one heavy chain and one light chain, while in other cases, variant forms contain two variable light chains and two variable heavy chains (or sub-portions thereof). The skilled artisan will be able to determine suitable variants of the antigen binding domains as shown herein using well known techniques. In certain embodiments, one skilled in the art can identify suitable regions of a molecule by targeting regions that are not considered important for activity, which can be altered without disrupting activity.
In certain specific embodiments, the polypeptide structure of the antigen binding domain is antibody-based, including, but not limited to, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimics"), chimeric antibodies, humanized antibodies, human antibodies, antibody fusions (sometimes referred to herein as "antibody conjugates"), and fragments thereof, respectively. In some embodiments, the antigen binding domain comprises or consists of an avimer.
In some embodiments, the antigen binding domain is an scFv.
In some embodiments, the antigen-selective CAR comprises a leader sequence or a signal peptide.
In other embodiments, the disclosure relates to isolated polynucleotides encoding any of the antigen binding domains described herein. In some embodiments, the disclosure relates to an isolated polynucleotide encoding a CAR. Also provided herein are vectors comprising the polynucleotides and methods of their preparation.
In other embodiments, the disclosure relates to isolated polynucleotides encoding any of the antigen binding domains described herein. In some embodiments, the disclosure relates to an isolated polynucleotide encoding a CAR. Also provided herein are vectors comprising the polynucleotides and methods of their preparation.
In some embodiments, a CAR immune cell (e.g., CAR-T cell) comprising a polynucleotide encoding a safety switch polypeptide (e.g., RQR 8) can form a component of a cell population produced by practicing the methods of the present disclosure. See, for example, WO2013153391a, which is hereby incorporated by reference in its entirety. In a CAR immune cell (e.g., CAR-T cell) comprising a polynucleotide, the safety switch polypeptide can be expressed on the surface of the CAR immune cell (e.g., CAR-T cell).
Hinge domain
The extracellular domain of a CAR of the present disclosure may comprise a "hinge" domain (or hinge region). The term generally refers to any polypeptide that has the function of linking a transmembrane domain in a CAR to an extracellular antigen binding domain in a CAR. In particular, hinge domains can be used to provide greater flexibility and accessibility to extracellular antigen binding domains.
The hinge domain may comprise up to 300 amino acids-in some embodiments 10 to 100 amino acids or in some embodiments, 25 to 50 amino acids. The hinge domain may be derived from all or a portion of a naturally occurring molecule, such as all or a portion of an extracellular region from CD8, CD4, CD28, 4-1BB, or IgG (in particular, the hinge region of IgG; it should be understood that the hinge region may contain a member of the immunoglobulin family, such as some or all of IgG1, igG2, igG3, igG4, igA, igD, igE, igM, or fragments thereof), or from all or a portion of an antibody heavy chain constant region. Alternatively, the hinge domain may be a synthetic sequence corresponding to a naturally occurring hinge sequence, or may be a fully synthetic hinge sequence. In some embodiments, the hinge domain is part of a human CD8 a chain (e.g., np_ 001139345.1). In other embodiments, the hinge and transmembrane domain comprises a portion of a human CD8 a chain. In some embodiments, the hinge domain of a CAR described herein comprises a subsequence of CD8 a, igG1, igG4, PD-1, or fcyriiia, particularly the hinge region of any of CD8 a, igG1, igG4, PD-1, or fcyriiia. In some embodiments, the hinge domain comprises a human CD8 a hinge, a human IgG1 hinge, a human IgG4, a human PD-1, or a human fcyriii a hinge. In some embodiments, a CAR disclosed herein comprises an scFv, a CD8 a human hinge and transmembrane domain, a CD3 zeta signaling domain, and a 4-1BB signaling domain.
Transmembrane domain
The CARs of the present disclosure are designed to have a transmembrane domain fused to the extracellular domain of the CAR. It may be similarly fused to the intracellular domain of the CAR. In some cases, the transmembrane domains may be selected or modified by amino acid substitutions to avoid binding of such domains to transmembrane domains of the same or different surface membrane proteins, thereby minimizing interactions with other members of the receptor complex. In some embodiments, the short linker can form a linkage between any one or some of the extracellular, transmembrane, and intracellular domains of the CAR.
Suitable transmembrane domains of the CARs disclosed herein have the following capabilities: (a) Expressing immune cells, such as but not limited to lymphocytes, such as T helper cells (T h ) Cytotoxic T (T) c ) Cell, T regulatory (T) reg ) A cell or Natural Killer (NK) cell, and/or (b) interact with an extracellular antigen binding domain and an intracellular signaling domain to direct a cellular response of an immune cell against a target cell.
The transmembrane domain may be derived from natural or synthetic sources. When the source is natural, the domain may be derived from any membrane-bound or transmembrane protein.
The transmembrane region particularly useful in the present disclosure may be derived from (including, or corresponds to) CD28, OX-40, 4-1BB/CD137, CD2, CD7, CD27, CD30, CD40, programmed death-1 (PD-1), induced T cell costimulatory molecules (ICOS), lymphocyte function-associated antigen-1 (LFA-1, CD1-1a/CD 18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT, (TNFSF 14), NKG2C, ig alpha (CD 79 a), DAP-10, fgamma receptor, MHC class 1 molecules, TNF receptor proteins, immunoglobulins, cytokine receptors, integrins, signaling lymphocyte activating molecules (SLAM proteins), activated NK cell receptors, BTLA, toll ligand receptors, ICAM-1, B7-H3, CDS, ICAM-1, CDS, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF 1), NKp44, NKp30, NKp46, CD19, CD4, CD8α, CD8β, IL-2Rβ, IL-2Rγ, IL-7Rα, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49 56103, ITGAL, CD1 1a, LFA-1, ITGAM, CD1 1B, ITGAX, CD1 1c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD 226), SLAMF4 (CD 244, 2B 4), CD84, CD96 (Tatile), CEACAM1, CRT AM, ly9 (CD 229), CD160 (55), PS1, CD100 (SEMA 4), CD69, CD6 (SLAM35F 108), SLAM35F 1 (SLAM35F 1 ) CD150, IPO-3), BLAME (SLAMF 8), SELPLG (CD 162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, a ligand that specifically binds to CD83, or any combination thereof.
As non-limiting examples, the transmembrane region may be derived from or part of a T cell receptor, such as α, β, γ or δ, a polypeptide constituting the CD3 complex, the IL-2 receptor p55 (α chain), p75 (β chain) or γ chain, a subunit chain of an Fc receptor, in particular fcγ receptor III or CD protein. Alternatively, the transmembrane domain may be synthetic and may comprise predominantly hydrophobic residues, such as leucine and valine. In some embodiments, the transmembrane domain is derived from a human CD8 a chain (e.g., np_ 001139345.1).
In some embodiments, the transmembrane domain in a CAR of the present disclosure is a CD8 a transmembrane domain.
In some embodiments, the transmembrane domain in a CAR of the present disclosure is a CD28 transmembrane domain.
intracellular domain
The intracellular (cytoplasmic) domain of the CARs of the disclosure can provide for activation of at least one of the normal effector functions of immune cells comprising the CARs. For example, the effector function of a T cell may refer to cell lysis activity or helper cell activity, including secretion of cytokines.
In some embodiments, the activated intracellular signaling domain for use in a CAR can be, for example (but is not limited to), a cytoplasmic sequence of a T cell receptor and a co-receptor that coordinates to initiate signal transduction upon antigen receptor binding, as well as any derivative or variant of these sequences and any synthetic sequences having the same functional capabilities.
It will be appreciated that suitable (e.g., activating) intracellular domains include, but are not limited to, signaling domains derived from (or corresponding to) the following: CD28, OX-40, 4-1BB/CD137, CD2, CD7, CD27, CD30, CD40, programmed death-1 (PD-1), induced T cell costimulatory molecules (ICOS), lymphocyte function-associated antigen-1 (LFA-1, CD1-1a/CD 18), CD3 gamma, CD3 delta, D3 epsilon, CD247, CD276 (B7-H3), LIGH, (TNFSF 14), NKG2C, ig alpha (CD 79 a), DAP-10, fgamma receptor, MHC 1 class molecules, TNF receptor proteins, immunoglobulin proteins, cytokine receptors, integrins, signaling lymphocyte activating molecules (SLAM proteins), activated NK cell receptors, BTLA, toll ligand receptors, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), RDS2, AMF7, NKp80 (KLRF 1), NKp44, NKp30, p46, CD19, CD8, IL-beta, IL-2, IL-beta, IL-R2, IL-gamma, IL-R4, ITgamma, IL-R2, and ITgamma, ITR 4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 1D, ITGAE, CD103, ITGAL, CD1 1a, LFA-1, ITGAM, CD1 1B, ITGAX, CD1 1c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD 226), SLAMF4 (CD 244, 2B 4), CD84, CD96 (Tactile), CEACAM1, CRT AM, ly9 (CD 229), CD160 (BY 55), PSGL1, CD100 (SEMA 4D), CD69, SLAMF6 (NTB-A, ly 108), SLAM (SLAMF 1, CD150, IPO-3), BLAMME (SLAMF 8), SELPLG (CD 162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, a ligand that specifically binds to CD83, or any combination thereof.
The intracellular domains of the CARs of the present disclosure, in addition to the activation domains described above, can also incorporate costimulatory signaling domains (interchangeably referred to herein as costimulatory molecules) to increase their potency. The co-stimulatory domain may provide a signal other than the primary signal provided by the activating molecule as described herein.
It will be appreciated that suitable costimulatory domains within the scope of the present disclosure may originate from (or correspond to), for example, CD28, OX40, 4-1BB/CD137, CD2, CD3 (α, β, δ, ε, γ, ζ), CD4, CD5, CD7, CD9, CD16, CD22, CD27, CD30, CD33, CD37, CD40, CD45, CD64, CD80, CD86, CD134, CD137, CD154, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1 (CD 1 1a/CD 18), CD247, CD276 (B7-H3), LIGHT (tumor necrosis factor superfamily member 14; TNFSF 14), NKG2C, ig α (CD 79 a), DAP-10, fc gamma receptor, MHC class I molecule, TNFR, integrin, signaling lymphocyte activating molecule, BTLA, toll ligand receptor, ICAM-1, B7-H3, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHT), LIGHT; kiRDS2, SLAMF7, NKp80 (KLRF 1), NKp44, NKp30, NKp46, CD19, CD4, CD8 alpha, CD8 beta, IL-2 Rbeta, IL-2 Rgamma, IL-7 Ralpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1-1D, ITGAE, CD103, ITGAL, CD1-1a, LFA-1, ITGAM, CD1-1B, ITGAX, CD1-1c, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, SLAMF1 (CD 226), SLAMF4 (CD 244, 2B 4), CD84, CD96 (Tactile), CEACAM1, CRT, ly9 (CD 229), CD160 (55), PS1, CD100 (CD 69), CD6, SLAMD 6 (SLAMF 6, SLAMF (37150), SLAMF (SLAMF 6) and SLAMF (SLAMF 6) IPO-3), BLAME (SLAMF 8), SELPLG (CD 162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, CD83 ligand, or fragments or combinations thereof. It is to be understood that additional costimulatory molecules, or fragments thereof, not listed above are within the scope of the present disclosure.
In some embodiments, the intracellular/cytoplasmic domain of the CAR can be designed to itself comprise the 4-1BB/CD137 domain or in combination with any other desired intracellular domain suitable for use in the context of the CARs of the present disclosure. The complete natural amino acid sequence of 4-1BB/CD137 is described in NCBI reference sequence: np_001552.2. The complete native 4-1BB/CD137 nucleic acid sequence is described in NCBI reference sequence: NM-001561.5.
In some embodiments, the intracellular/cytoplasmic domain of the CAR can be designed to comprise the CD28 domain itself or in combination with any other desired intracellular domain suitable for use in the context of the CARs of the present disclosure. The complete natural amino acid sequence of CD28 is described in NCBI reference sequence: np_006130.1. The complete native CD28 nucleic acid sequence is described in NCBI reference sequence: NM-006139.1.
In some embodiments, the intracellular/cytoplasmic domain of the CAR can be designed to itself comprise the cd3ζ domain or in combination with any other desired intracellular domain suitable for use in the context of the CARs of the present disclosure.
For example, the intracellular domain of the CAR may comprise a portion of the cd3ζ chain and a portion of a costimulatory signaling molecule. Intracellular signaling sequences within the intracellular signaling portion of the CARs of the disclosure may be linked to each other randomly or in a specified order. In some embodiments, the intracellular domain is designed to comprise an activation domain of cd3ζ and a signaling domain of CD 28. In some embodiments, the intracellular domain is designed to comprise an activation domain of CD3ζ and a signaling domain of 4-1 BB.
In some embodiments, the intracellular signaling domain of a CAR of the present disclosure comprises a domain of a co-stimulatory molecule. In some embodiments, the intracellular signaling domain of a CAR of the present disclosure comprises a portion of a costimulatory molecule selected from the group consisting of fragments of 4-1BB (GenBank: AAA 53133) and CD28 (NP 006130.1).
Engineered immune cells comprising a CAR
Also provided herein are engineered immune cells and CAR-expressing engineered immune cell populations (e.g., CAR-T cells or car+ cells), each of which is depleted of cells expressing an endogenous TCR.
In some embodiments, the engineered immune cells include CAR T cells, each CAR T cell comprising an extracellular antigen binding domain and expression of an endogenous TCR is reduced or eliminated. In some embodiments, the engineered immune cell population comprises a population of CAR T cells, each CAR T cell comprising two or more different extracellular antigen-binding domains and expression of the endogenous TCR is reduced or eliminated. In some embodiments, the immune cells comprise a population of CARs, each CAR T cell comprising the same extracellular antigen binding domain and expression of the endogenous TCR is reduced or eliminated.
The engineered immune cells may be allogeneic or autologous.
In some embodiments, the engineered immune cell or population of engineered immune cells is a T cell (e.g., an inflammatory T lymphocyte cytotoxic T lymphocyte, regulatory T lymphocyte, helper T lymphocyte, tumor Infiltrating Lymphocyte (TIL)), NK cell, NK-T cell, TCR expressing cell, dendritic cell, killer dendritic cell, mast cell, or B cell, and expresses the CAR. In some embodiments, the T cells may be derived from the group consisting of: cd4+ T lymphocytes, cd8+ T lymphocytes, or a population comprising a combination of cd4+ and cd8+ T cells.
In some embodiments, the engineered immune cells or populations of engineered immune cells produced using the disclosed methods can be derived from, for example, but are not limited to, stem cells. The stem cells may be adult stem cells, non-human embryonic stem cells, more specifically non-human stem cells, umbilical cord blood stem cells, progenitor cells, bone marrow stem cells, induced pluripotent stem cells, totipotent stem cells, or hematopoietic stem cells.
In some embodiments, the engineered immune cells or populations of immune cells produced using the disclosed methods are obtained from or prepared from peripheral blood. In some embodiments, the engineered immune cells are obtained from or prepared from Peripheral Blood Mononuclear Cells (PBMCs). In some embodiments, the engineered immune cells are obtained from or prepared from bone marrow. In some embodiments, the engineered immune cells are obtained from or prepared from umbilical cord blood. In some embodiments, the cell is a human cell. In some embodiments, the cell is transfected or transduced with a nucleic acid vector using a method selected from the group consisting of: electroporation, sonoporation, biolistics (e.g., gene gun), lipofection, polymer transfection, nanoparticles, viral transfection (e.g., retrovirus, lentivirus, AAV), or polyplex.
In some embodiments, the engineered immune cells expressing the antigen specific CAR at the cell surface membrane comprise greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% stem cell memory and central memory cells.
In some embodiments, the engineered immune cells expressing the antigen-specific CAR at the cell surface membrane comprise a percentage of stem cell memory and central memory cells of about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 15% to about 50%, about 15% to about 40%, about 20% to about 60%, or about 20% to about 70%.
In some embodiments, the engineered immune cells expressing antigen-specific CARs at the cell surface membrane are enriched in T CM And/or T SCM Cells such that the engineered immune cells comprise at least about 60%, 65%, 70%, 75% or 80% of combined T CM And T SCM And (3) cells. In some embodiments, the engineered immune cells expressing antigen-specific CARs at the cell surface membrane are enriched in T CM And/or T SCM Cells such that the engineered immune cells comprise at least about 70% of combined T CM And T SCM And (3) cells. In some embodiments, the engineered immune cells expressing antigen-specific CARs at the cell surface membrane are enriched in T CM And/or T SCM Cells such that the engineered immune cells comprise at least about 75% of combined T CM And/or T SCM And (3) cells.
In some embodiments, the engineered immune cell is a CAR-expressing inflammatory T lymphocyte. In some embodiments, the engineered immune cell is a CAR-expressing cytotoxic T lymphocyte. In some embodiments, the engineered immune cell is a CAR-expressing regulatory T lymphocyte. In some embodiments, the engineered immune cell is a CAR-expressing helper T lymphocyte.
Genetic modification of CAR T cells
In some embodiments, an engineered immune cell according to the present disclosure may comprise one or more disrupted or inactivated genes. In some embodiments, the gene of the target antigen (e.g., EGFRvIII, flt3, WT-1, CD20, CD23, CD30, CD38, CD33, CD133, MHC-WT1, TSPAN10, MHC-PRAME, liv1, ADAM10, chra 2, leY, NKGD2D, CS1, CD44v6, ROR1, claudin) -18.2, muc17, fapα, ly6G6D, c orf23, G6D, MEGT1, NG25, CD19, BCMA, flt3, CD70, DLL3 or CD34, CD 70) can be knocked down to induce binding of the same antigen-targeted CAR (e.g., EGFRvIII, flt3, WT-1, CD20, CD23, CD30, CD38, CD33, CD133, MHC-WT1, TSPAN10, MHC-PRAME, liv1, ADAM10, chra 2, leY, nk2, fapα, ly6G6D, c orf23, G6D, MEGT1, NG25, CD19, BCMA, flt3, DLL3 or CD34, CD 70) to avoid activation of the same antigen (e.g., egfrvv 3, flv 3, CD34, CD 70). As described herein, in some embodiments, an engineered immune cell according to the present disclosure comprises a disrupted or inactivated gene selected from the group consisting of: MHC1 (. Beta.2M), MHC2 (CIITA), EGFRvIII, flt3, WT-1, CD20, CD23, CD30, CD38, CD33, CD133, MHC-WT1, TSPAN10, MHC-PRAME, liv1, ADAM10, CHRNA2, leY, NKGD2D, CS1, CD44v6, ROR1, tight junction protein (Claudin) -18.2, muc17, FAP alpha, ly6G6D, c6orf23, G6D, MEGT1, NG25, CD19, BCMA, FLT3, CD70, DLL3 or CD34, CD70, TCR alpha and TCR beta, and/or expression of CAR or multi-chain CAR. In some embodiments, the cell comprises a multi-chain CAR. In some embodiments, the isolated cell comprises two disrupted or inactivated genes selected from the group consisting of: CD52 and tcra, CDR52 and tcra, PD-1 and tcra, MHC2 and tcra, and/or express a CAR or a multi-chain CAR.
In some embodiments, an engineered immune cell according to the present disclosure comprises a disrupted or inactivated gene selected from the group consisting of: CD52, DLL3, GR, PD-1, CTLA-4, LAG3, TIM3, BTLABY55, TIGIT, B7H5, LAIR1, SIGLEC10, 2B4, HLA, TCRα and TCRβ, and/or expressed CAR, multi-chain CAR and/or pTβ1 transgenes. In some embodiments, the isolated cell comprises a polynucleotide encoding a polypeptide comprising a multi-chain CAR. In some embodiments, an isolated cell according to the present disclosure comprises two disrupted or inactivated genes selected from the group consisting of: CD52 and GR, CD52 and TCRβ3, CDR52 and TCRβ0, DLL3 and CD52, DLL3 and TCRβ5, DLL3 and TCRβ2, GR and TCRβ7, GR and TCRβ4, TCRβ9 and TCRβ6, PD-1 and TCRβ8, CTLA-4 and TCRα1, CTLA-4 and TCRα0, LAG3 and TCRα3, LAG3 and TCRα2, TIM3 and TCRα5, tim3 and TCRα4, BTLA and TCRα7, BTLA and TCRα6, BY55 and TCRα9, BY55 and TCRα8, TIGIT and TCRα0, B7H5 and TCRα2, LAIR1 and TCRα3, LAGLEC 10 and α, SIGLEC10 and β, 2B4 and TCRα, and TCR α2B4 and TCR α, and pT α, or multiple genes including pTC and/or multiple expression of CAR chains. In some embodiments, the methods comprise disrupting or inactivating one or more genes by introducing into the cell an endonuclease capable of selectively inactivating the genes by selective DNA cleavage. In some embodiments, the endonuclease may be, for example, a Zinc Finger Nuclease (ZFN), homing endonuclease (megaTAL) nuclease, meganuclease, transcription activator-like effector nuclease (TALE-nuclease, or ) Or a CRISPR (e.g., cas9 or Cas 12) endonuclease.
In some embodiments, TCRs are rendered non-functional in cells according to the present disclosure by disruption or inactivation of the tcra gene and/or tcrp gene. In some embodiments, a method of obtaining a modified cell derived from an individual is provided, wherein the cell can proliferate independent of a Major Histocompatibility Complex (MHC) signaling pathway. Modified cells that can proliferate independent of MHC signaling pathways, readily obtainable by this method, are encompassed within the scope of the present disclosure. The modified cells disclosed herein can be used to treat host-versus-graft (HvG) rejection and graft-versus-host disease (GvHD) in a patient in need thereof; accordingly, within the scope of the present disclosure is a method of treating host-versus-graft (HvG) rejection and graft-versus-host disease (GvHD) in a patient in need thereof, the method comprising treating the patient by administering to the patient an effective amount of modified cells comprising disrupted or inactivated TCR a and/or TCR β genes.
The present disclosure provides methods of determining the purity of an engineered immune cell population that lacks or has reduced endogenous TCR expression. In some embodiments, the engineered immune cell comprises less than 5.0%, less than 4.0%, less than 3.0% tcr+ cells, less than 2.0% tcr+ cells, less than 1.0% tcr+ cells, less than 0.9% tcr+ cells, less than 0.8% tcr+ cells, less than 0.7% tcr+ cells, less than 0.6% tcr+ cells, less than 0.5% tcr+ cells, less than 0.4% tcr+ cells, less than 0.3% tcr+ cells, less than 0.2% tcr+ cells, or less than 0.1% tcr+ cells. Such populations may be the products of the disclosed methods.
In some embodiments, the immune cells are engineered to be resistant to one or more chemotherapeutic agents. The chemotherapeutic agent may be, for example, a Purine Nucleotide Analogue (PNA), thereby making the immune cell suitable for use in cancer therapy in combination with adoptive immunotherapy and chemotherapy. Exemplary PNAs include, for example, clofarabine (clofaabine), fludarabine (fludarabine), and cyclophosphamide and cytarabine, alone or in combination. PNA is a PNA metabolized to mono-, di-, and triphosphate by deoxycytidine kinase (dCK). Its triphosphate form competes with ATP for DNA synthesis, acts as a pro-apoptotic agent, and is a potent inhibitor of ribonucleotide reductase (RNR) involved in trinucleotide production.
In some embodiments, an isolated cell or cell line of the present disclosure may comprise pta or a functional variant thereof. In some embodiments, the isolated cell or cell line may be further genetically modified by disruption or inactivation of the tcra gene.
The present disclosure also provides an engineered immune cell comprising any of the CAR polynucleotides described herein. In some embodiments, the CAR can be introduced into immune cells via a plasmid vector as a transgene. In some embodiments, the plasmid vector may also contain, for example, a selectable marker that provides for identification and/or selection of cells that receive the vector.
After introducing the polynucleotide encoding the CAR polypeptide into a cell, the CAR polypeptide can be synthesized in situ in the cell. Alternatively, the CAR polypeptide can be produced extracellularly and subsequently introduced into the cell. Methods of introducing polynucleotide constructs into cells are known in the art. In some embodiments, stable transformation methods (e.g., using lentiviral vectors) can be used to integrate the polynucleotide construct into the genome of a cell. In other embodiments, transient transformation methods may be used to transiently express polynucleotide constructs and polynucleotide constructs that are not integrated into the genome of a cell. In other embodiments, virus-mediated methods may be used. The polynucleotide may be introduced into the cell by any suitable means, such as recombinant viral vectors (e.g., retroviruses, adenoviruses), liposomes, and the like. Transient transformation methods include, for example (but are not limited to), microinjection, electroporation, or particle bombardment. The polynucleotide may be included in a vector, such as a plasmid vector or a viral vector.
In some embodiments, an isolated nucleic acid is provided comprising a promoter operably linked to a first polynucleotide encoding an antigen binding domain, at least one co-stimulatory molecule, and an activation domain. In some embodiments, the nucleic acid construct is contained within a viral vector. In some embodiments, the viral vector is selected from the group consisting of: retroviral vectors, murine leukemia viral vectors, SFG vectors, adenoviral vectors, lentiviral vectors, adeno-associated viral (AAV) vectors, herpes viral vectors, and vaccinia viral vectors. In some embodiments, the nucleic acid is contained within a plasmid.
In some embodiments, the isolated nucleic acid construct is contained within a viral vector and introduced into the genome of the engineered immune cell by random integration (e.g., lentivirus or retrovirus-mediated random integration). In some embodiments, the isolated nucleic acid construct is contained in a viral vector or a non-viral vector and is introduced into the genome of the engineered immune cell by site-specific integration (e.g., adenovirus-mediated site-specific integration).
3. Preparation of engineered immune cells (including CAR T cells)
Provided herein are methods of analyzing or determining various properties of engineered immune cells (including engineered immune cells, such as CAR expressing or car+ cells) from an immune cell population. As described herein, an engineered immune cell, such as a CAR T cell, can be modified to reduce or eliminate expression of an endogenous TCR, and the remaining tcr+ engineered immune cells can be knocked out at the end of production according to the methods described herein. The present disclosure provides methods of characterizing or analyzing an engineered immune cell population to characterize a drug product or as part of a manufacturing process. The present disclosure also provides methods of analyzing or determining other properties of engineered immune cells, such as potency or versatility, to characterize a drug product or as part of a manufacturing process. In some embodiments, the engineered immune cells (such as CAR T cells) are prepared according to Good Manufacturing Practice (GMP).
Many known techniques may be used to prepare polynucleotides, polypeptides, vectors, antigen binding domains, immune cells, compositions, and the like according to the present disclosure.
Cells may be obtained from a subject prior to in vitro manipulation or genetic modification of immune cells described herein. The CAR-expressing cells may be derived from allogeneic or autologous sources, and endogenous TCRs may be knocked out as described herein.
a. Source material
In some embodiments, the immune cells comprise T cells. T cells can be obtained from a number of sources, including Peripheral Blood Mononuclear Cells (PBMCs), bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from an infection site, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments, any number of techniques known to the skilled artisan may be used, such as FICOLL TM T cells are isolated from a blood volume collected from a subject.
Cells may be obtained from circulating blood of an individual by apheresis. Apheresis products typically contain lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated leukocytes, erythrocytes, and platelets. In certain embodiments, cells collected by apheresis may be washed to remove plasma components and then placed in an appropriate buffer or medium for subsequent processing.
In certain embodiments, for example, using a PERCOL TM Gradient centrifugation separates T cells from PBMCs by lysing erythrocytes and depleting monocytes. Specific subsets of T cells (e.g., cd28+, cd4+, cd45ra-and cd45ro+ T cells or cd28+, cd4+, cds+, cd45ra-, cd45ro+ and cd62l+ T cells) can be further isolated by positive or negative selection techniques known in the art. For example, enrichment of a T cell population by negative selection can be achieved with a combination of antibodies directed against surface markers unique to the cells selected negatively. One of the methods used herein is cell sorting and/or selection by negative magnetic immunoadhesion or flow cytometry using a mixture of monoclonal antibodies directed against cell surface markers present on negatively selected cells. For example, to enrich for cd4+ cells by negative selection, monoclonal antibody mixtures typically include antibodies to CD14, CD20, CD11b, CD16, HLA-DR, and CD 8. Flow cytometry and cell sorting may also be used to isolate a population of cells of interest for use in the present disclosure.
PBMCs may be used directly for genetic modification of immune cells (such as CARs or TCRs) using methods as described herein. In certain embodiments, after isolation of PBMCs, T lymphocytes may be further isolated, and cytotoxic and helper T lymphocytes may be sorted into subpopulations of naive, memory and effector T cells before or after genetic modification and/or expansion. In some embodiments, the cd8+ cells are further sorted into primordial, stem cell memory, central memory, and effector cells by identifying cell surface antigens associated with each of these cd8+ cell types. In some embodiments, the expression of the phenotype marker of the central memory T cell comprises CD27, CD45RA, CD45RO, CD62L, CCR, CD28, CD3, and CD127 and is negative for granzyme B. In some embodiments, the stem cell memory T cells are CD45RO-, cd62l+, cd8+ T cells. In some embodiments, the central memory T cells are cd45ro+, cd62l+, cd8+ T cells. In some embodiments, effector T cells are negative for CD62L, CCR7, CD28, and CD127, and positive for granzyme B and perforin. In certain embodiments, the cd4+ T cells are further sorted into subpopulations. For example, cd4+ T helper cells can be sorted into primordial, central memory, and effector cells by identifying a population of cells that have cell surface antigens.
b. Stem cell derived immune cells
In some embodiments, the immune cells may be derived from Embryonic Stem (ES) cells or Induced Pluripotent Stem (iPS) cells. Suitable HSCs, mesenchymal cells, iPS cells and other types of stem cells can be cultured into immortalized cell lines or isolated directly from the patient. Various methods for isolating, generating, and/or culturing stem cells are known in the art and may be used to practice the present disclosure.
In some embodiments, the immune cells are induced pluripotent stem cells (ipscs) derived from reprogrammed T cells. In some embodiments, the source material may be induced pluripotent stem cells (ipscs) derived from T cells or non-T cells. The source material may be embryonic stem cells. The source material may be B cells, or any other cells from a peripheral blood mononuclear cell isolate, hematopoietic progenitor cells, hematopoietic stem cells, mesenchymal stem cells, adipose stem cells, or any other somatic cell type.
c. Genetic modification of isolated cells
Immune cells, such as T cells, may be genetically modified after isolation using known methods, or immune cells may be activated and expanded in vitro (or differentiated in the case of progenitor cells) prior to being genetically modified. In some embodiments, the isolated immune cells are genetically modified to reduce or eliminate expression of endogenous tcra and/or CD 52. In some embodiments, the cells are genetically modified to reduce or eliminate expression of endogenous proteins (e.g., tcrα and/or CD 52) using gene editing techniques (e.g., CRISPR/Cas9, CRISPR/Cas12a, zinc Finger Nucleases (ZFNs), TALENs, homing endonucleases, meganucleases). In another embodiment, immune cells (such as T cells) are genetically modified (e.g., transduced with a viral vector comprising one or more CAR-encoding nucleotide sequences) with a chimeric antigen receptor described herein, followed by in vitro activation and/or expansion.
Certain methods for preparing the constructs and engineered immune cells of the present disclosure are described in PCT application PCT/US15/14520, the contents of which are incorporated herein by reference in their entirety.
It will be appreciated that PBMCs may also include other cytotoxic lymphocytes, such as NK cells or NKT cells. Expression vectors carrying coding sequences for chimeric receptors as disclosed herein can be introduced into a population of human donor T cells, NK cells, or NKT cells. Successfully transduced T cells carrying the expression vector can be sorted using flow cytometry to isolate CD3 positive T cells, and then further proliferated to increase the number of these CAR expressing T cells in addition to cell activation using anti-CD 3 antibodies and IL-2 or other methods as described elsewhere in the art. Standard procedures are used to cryopreserve CAR-expressing T cells for storage and/or preparation for use in human subjects. In one embodiment, in vitro transduction, culture, and/or expansion of T cells is performed in the absence of non-human animal derived products, such as fetal calf serum (fetal calf serum/fetal bovine serum).
To clone a polynucleotide, the vector may be introduced into a host cell (the host cell is isolated) to allow replication of the vector itself and thereby amplify a copy of the polynucleotide contained therein. Cloning vectors may contain sequence components, typically including but not limited to origins of replication, promoter sequences, transcription initiation sequences, enhancer sequences, and selectable markers. These elements may be selected as appropriate by one of ordinary skill in the art. For example, the origin of replication may be selected to promote autonomous replication of the vector in a host cell.
In certain embodiments, the disclosure provides isolated host cells comprising the vectors provided herein. Host cells containing the vector may be used for expression or cloning of the polynucleotide contained in the vector. Suitable host cells may include, but are not limited to, prokaryotic cells, fungal cells, yeast cells, or higher eukaryotic cells, such as mammalian cells, particularly human cells.
The vector may be introduced into the host cell using any suitable method known in the art, including, but not limited to, DEAE-dextran mediated delivery, calcium phosphate precipitation methods, cationic lipid mediated delivery, liposome mediated transfection, electroporation, gene gun methods, receptor mediated gene delivery, delivery mediated by polylysine, histones, chitosan, and peptides. Standard methods for transfecting and transforming cells for expression of vectors of interest are well known in the art. In another embodiment, a mixture of different expression vectors can be used to genetically modify a donor population of immune effector cells, wherein each vector encodes a different CAR as disclosed herein. The resulting transduced immune effector cells form a mixed population of engineered cells, wherein a proportion of the engineered cells express more than one different CAR.
In one embodiment, the present disclosure provides a method of storing genetically engineered cells expressing a CAR or TCR. This involves cryopreserving immune cells so that the cells remain viable after thawing. A portion of the CAR-expressing immune cells can be cryopreserved by methods known in the art to provide a permanent source of such cells for future treatment of patients with malignancy. The cryopreserved transformed immune cells can be thawed, grown, and expanded, if desired, to yield more such cells.
In some embodiments, the cells are formulated by first collecting the cells from their culture medium, and then washing and concentrating the cells in a medium and container system ("pharmaceutically acceptable" carrier) suitable for administration in a therapeutically effective amount. Suitable infusion media can be any isotonic medium formulation, typically normal saline Normosol TM R (yaban) or Plasma-Lyte TM A (bucktar), but 5% dextrose in water or Ringer's lactate may also be used. Infusion medium may be supplemented with human serum albumin.
d. Allogeneic CAR T cells
The process for preparing allogeneic CAR T therapies involves harvesting healthy, selected, screened, and tested T cells from healthy donors. T cells are then engineered to express CARs that recognize certain cell surface proteins expressed in blood or solid tumors. Allogeneic T cells are genetically edited to reduce the risk of graft versus host disease (GvHD) and to prevent allograft rejection. T cell receptor genes (e.g., tcrα, tcrβ) are knocked out to avoid GvHD. The CD52 gene can be knocked out to render the CAR T product resistant to anti-CD 52 antibody treatment. anti-CD 52 antibody therapy can therefore be used to suppress the host immune system and allow the CAR T to remain implanted to achieve full therapeutic effect. The engineered T cells are then subjected to a purification step and eventually cryopreserved in vials for delivery to the patient.
e. Autologous CAR T cells
Autologous Chimeric Antigen Receptor (CAR) T cell therapy involves collecting cells of the patient themselves (e.g., leukocytes, including T cells) and genetically engineering the T cells to express CARs that recognize targets expressed on the cell surface of one or more specific cancer cells and kill the cancer cells. The engineered cells are then cryopreserved and subsequently administered to a patient.
4. In vitro sorting method
In some embodiments, methods are provided for in vitro sorting of immune cell populations, wherein a subpopulation of immune cell populations comprises engineered immune cells expressing an antigen-specific CAR comprising an epitope (e.g., an exemplary mimotope sequence) specific for a monoclonal antibody. The method comprises contacting a population of immune cells with a monoclonal antibody specific for the epitope, and selecting immune cells that bind to the monoclonal antibody to obtain a population of cells enriched for engineered immune cells expressing antigen-specific CARs.
In some embodiments, the monoclonal antibody specific for the epitope is optionally conjugated to a fluorophore. In this embodiment, the step of selecting cells that bind to the monoclonal antibody can be accomplished by Fluorescence Activated Cell Sorting (FACS).
In some embodiments, the monoclonal antibody specific for the epitope is optionally conjugated to a magnetic particle. In this embodiment, the step of selecting cells that bind to the monoclonal antibody can be performed by Magnetic Activated Cell Sorting (MACS).
In some embodiments, the mAb used in the method of sorting immune cells expressing a CAR is selected from alemtuzumab, ibritumomab, moruzumab-CD 3 (murominab-CD 3), toximomab, acipimab, basiliximab (basiliximab), cetuximab, infliximab, rituximab, bevacizumab, pegylated cetuximab, daclizumab, elkumezumab (eclipzumab), efalizumab (efalizumab), gemtuzumab, natalizumab, omalizumab (palivizumab), lanbizumab (ranibizumab), tositumomab, trastuzumab, vedolizumab (vedolizumab), adalimab, bevacizumab, oxuzumab, ofuzumab (efalizumab), gefarizumab (efalizumab), gemtuzumab, paltuzumab (palivizumab), paltuzumab, or other than one. In some embodiments, the mAb is rituximab. In another embodiment, the mAb is QBEND-10. In other embodiments, the mAb binds to tcra or tcrp.
In some embodiments, the population of CAR-expressing immune cells obtained when using the method for in vitro sorting CAR-expressing immune cells described above comprises at least 70%, 75%, 80%, 85%, 90%, 95% of CAR-expressing immune cells. In some embodiments, the population of CAR-expressing immune cells obtained when using the method for sorting CAR-expressing immune cells in vitro comprises at least 85% CAR-expressing immune cells.
In some embodiments, the population of CAR-expressing immune cells obtained when using the method for in vitro sorting of CAR-expressing immune cells described above exhibits increased in vitro cytotoxic activity compared to the initial (unsorted) population of cells. In some embodiments, the in vitro cytotoxic activity is increased by 10%, 20%, 30%, 40% or 50%. In some embodiments, the immune cell is a T cell.
In some embodiments, the mAb was previously bound to a support or surface. Non-limiting examples of solid supports may include beads, agarose beads, magnetic beads, plastic well plates, glass well plates, ceramic well plates, columns, or cell culture bags.
CAR-expressing immune cells to be administered to a subject can be enriched in vitro from a source population. Methods of expanding a source population may include selecting cells expressing an antigen (such as CD34 antigen) using a combination of density centrifugation, immunomagnetic bead purification, affinity chromatography, and fluorescence activated cell sorting.
Flow cytometry can be used to quantify specific cell types within a cell population. In general, flow cytometry is a method of quantifying components or structural features of cells, mainly by optical means. Since different cell types can be distinguished by quantifying structural features, flow cytometry and cell sorting can be used to count and sort cells of different phenotypes in a mixture.
In some embodiments, the method for sorting CAR-expressing T cells is Magnetically Activated Cell Sorting (MACS). Magnetically Activated Cell Sorting (MACS) is a method of separating various cell populations from cell surface antigens (e.g., CD molecules) by using superparamagnetic nanoparticles and columns. MACS can be used to obtain pure cell populations. Cells in a single cell suspension may be magnetically labeled with microbeads. The sample was applied to a column consisting of ferromagnetic spheres covered with a cell-friendly coating allowing rapid and gentle separation of cells. Unlabeled cells will pass through while magnetically labeled cells remain in the column. The flow-through may be collected as an unlabeled cell fraction. After the washing step, the column is removed from the separator and the magnetically labeled cells are eluted from the column.
Detailed protocols for purifying specific cell populations (e.g., T cells) can be found in Basu S et al (2010). (Basu S, campbell HM, dittel BN, ray A. Purification of specific cell population by Fluorescence Activated Cell Sorting (FACS). J Vis exp. (41): 1546).
5. Pharmaceutical composition and therapy
In some embodiments, the cells are formulated by first collecting the cells from their culture medium, and then washing and concentrating the cells in a medium and container system ("pharmaceutically acceptable" carrier) suitable for administration in a therapeutically effective amount. Suitable infusion media can be any isotonic medium formulation, typically normal saline Normosol TM R (yaban) or Plasma-Lyte TM A (bucktar), but 5% dextrose in water or Ringer's lactate may also be used. Infusion medium may be supplemented with human serum albumin.
In embodiments, the desired therapeutic amount of cells in the composition is typically at least 2 cells (e.g., at least 1 cd8+ central or stem cell memory T cell and at least 1 cd4+ helper T cell subset; or two or more cd8+ central or stem cell memory T cells; or two or more cd4+ helper T cell subsets) or more typically greater than 10 2 Individual cells, and up to and including 10 6 Individual cells up to and including 10 7 、10 8 Or 10 9 Individual cells, and may be more than 10 10 Individual cells. The number of cells will depend on the intended use of the composition and the type of cells included therein. The density of the desired cells is generally greater than 10 6 Individual cells/ml, and is generally greater than 10 7 Individual cells/ml, typically 10 8 Individual cells/ml or greater. The clinically relevant number of immune cells can be apportioned to accumulate at or above 10 5 、10 6 、10 7 、10 8 、10 9 、10 10 、10 11 Or 10 12 Multiple infusions of individual cells. In some aspects of the disclosure, particularly since all infused cells will be redirected to a particular target antigen, an administration of about 10 may be possible 5 Per kilogram or about 10 6 Kilogram%Each patient 10 6 -10 11 ) Lower numbers of cells within the range. CAR treatment may be administered multiple times at doses within these ranges. The cell pairs may be autologous, allogenic or xenogenic to the patient being treated.
The CAR-expressing cell populations of the present disclosure can be administered alone or in a pharmaceutical composition in combination with a diluent and/or with other components (e.g., IL-2 or other cytokines or cell populations). The pharmaceutical compositions of the present disclosure may comprise a population of CAR-expressing or TCR-expressing cells, such as T cells described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents, or excipients. Such compositions may comprise buffers, such as neutral buffered saline, phosphate buffered saline, and the like; carbohydrates, such as glucose, mannose, sucrose or dextran, mannitol; a protein; polypeptides or amino acids, such as glycine; an antioxidant; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and (3) a preservative. The compositions of the present disclosure are preferably formulated for intravenous administration.
The pharmaceutical composition (solution, suspension, etc.) may comprise one or more of the following: sterile diluents, such as water for injection, saline solution (preferably physiological saline), ringer's solution, isotonic sodium chloride; fixed oils such as synthetic mono-or diglycerides which can act as solvents or suspending media; polyethylene glycol, glycerol, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamine tetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for modulating tonicity, such as sodium chloride or dextrose. The parenteral formulation may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The injectable pharmaceutical composition is preferably sterile.
6. Therapeutic method
The present disclosure includes methods for treating or preventing a disease (e.g., cancer) in a patient, the methods comprising administering to a patient in need thereof an effective amount of CAR T cells or engineered immune cells comprising a CAR disclosed herein. In some embodiments, an effective amount of CAR T cells or engineered immune cells have been analyzed for various properties according to the methods described in the present disclosure. In some embodiments, CAR T cell drugs for therapeutic use have been analyzed for various properties (such as potency or versatility) according to the methods described in the present disclosure. In some embodiments, the CAR T cells are TCR-CAR T cells, and CAR T drugs for therapeutic use have been analyzed for various attributes, such as the number or percentage of tcr+car T cells remaining and/or potency or versatility, according to the methods described in the present disclosure.
Methods for treating diseases or disorders, including cancer, are provided. In some embodiments, the disclosure relates to producing a T cell-mediated immune response in an individual comprising administering to the individual an effective amount of an engineered immune cell of the application. In some embodiments, the T cell mediated immune response is directed against a target cell or cells. In some embodiments, the engineered immune cell comprises a Chimeric Antigen Receptor (CAR). In some embodiments, the target cell is a tumor cell. In some aspects, the disclosure comprises a method for treating or preventing a malignancy, the method comprising administering to an individual in need thereof an effective amount of at least one isolated antigen-binding domain described herein. In some aspects, the disclosure comprises a method for treating or preventing a malignancy, the method comprising administering to a subject in need thereof an effective amount of at least one immune cell, wherein the immune cell comprises at least one chimeric antigen receptor, T cell receptor, and/or isolated antigen binding domain as described herein. The CAR-containing immune cells of the present disclosure are useful for treating malignancies involving aberrant expression of biomarkers. In some embodiments, the CAR-containing immune cells of the present disclosure can be used to treat small cell lung cancer, melanoma, low grade glioma, glioblastoma, medullary thyroid carcinoma, carcinoid, diffuse neuroendocrine tumors in the pancreas, bladder and prostate, testicular cancer, and lung adenocarcinoma with neuroendocrine features. In exemplary embodiments, CAR-containing immune cells (e.g., CAR-T cells of the present disclosure) are used to treat small cell lung cancer.
Also provided are methods for reducing tumor size in a subject comprising administering to a subject an engineered cell of the disclosure, wherein the cell comprises a chimeric antigen receptor comprising an antigen binding domain and binding to an antigen on a tumor.
In some embodiments, the subject has a solid tumor or hematological malignancy, such as lymphoma or leukemia. In some embodiments, the engineered cells are delivered to a tumor bed. In some embodiments, the cancer is present in the bone marrow of the individual. In some embodiments, the engineered cell is an autoimmune cell, such as an autologous T cell. In some embodiments, the engineered cell is an allogeneic immune cell, e.g., an allogeneic T cell. In some embodiments, the engineered cell is a heterologous immune cell, e.g., a heterologous T cell. In some embodiments, the engineered cells of the application are transfected or transduced in vivo. In other embodiments, the engineered cells are transfected or transduced ex vivo. As used herein, the term "in vitro cell" refers to any cell that is cultured ex vivo.
A therapeutic agent, e.g., an "therapeutically effective amount", "an effective dose", "an effective amount", or "a therapeutically effective dose" of an engineered CART cell, is any amount that, when used alone or in combination with another therapeutic agent, protects an individual from onset of a disease or promotes regression of a disease as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free symptomatic periods, or prevents a disorder or disability resulting from a disease affliction. The ability of a therapeutic agent to promote regression of a disease can be assessed using a variety of methods known to the skilled practitioner, for example, in a human individual during a clinical trial, in an animal model system that predicts efficacy in humans, or by analyzing the activity of the agent in an in vitro assay.
The terms "patient" and "individual" are used interchangeably and include human and non-human animal individuals as well as those individuals with formally diagnosed disorders, those individuals without formally identified disorders, those individuals under medical observation, those individuals at risk of developing a disease, and the like.
The term "treatment" includes therapeutic treatment, prophylactic treatment, and the use of one of the terms to reduce the risk that a subject will develop a disorder or other risk factor. Treatment does not require complete cure of the condition and encompasses one embodiment in which symptoms or potential risk factors are reduced. The term "preventing" does not require 100% elimination of the possibility of an event occurring. In particular, it means that the likelihood of occurrence of an event in the presence of a compound or method has been reduced.
The desired therapeutic amount of cells in the composition is typically at least 2 cells (e.g., at least 1 cd8+ central memory T cell and at least 1 subset of cd4+ helper T cells), or more typically greater than 10 2 Individual cells, and up to 10 6 Up to and including 10 8 Or 10 9 Individual cells, and can exceed 10 10 Individual cells. The number of cells will depend on the intended use of the composition and the type of cells included therein. The density of the desired cells is generally greater than 10 6 Individual cells/ml, and is generally greater than 10 7 Individual cells/ml, typically 108 cells/ml or greater. The clinically relevant number of immune cells can be apportioned to accumulate at or above 10 5 、10 6 、10 7 、10 8 、10 9 、10 10 、10 11 Or 10 12 Multiple infusions of individual cells. In some aspects of the disclosure, specifically, since all infused cells will be redirected to a particular target antigen, they can be administered at 10 6 Kg (per patient 10 6 -10 11 ) Lower numbers of cells within the range. CAR treatment may be administered multiple times at doses within these ranges. The cell pairs may be autologous, allogenic or xenogenic to the patient being treated.
In some embodiments, the therapeutically effective amount of CAR T cells is about 1 x 10 5 Individual cells/kg, about 2X 10 5 Individual cells/kg, about 3X 10 5 Individual cells/kg, about 4X 10 5 Individual cells/kg, about 5X 10 5 Individual cells/kg, about6×10 5 Individual cells/kg, about 7X 10 5 Individual cells/kg, about 8X 10 5 Individual cells/kg, about 9X 10 5 Individual cells/kg, 2X 10 6 Cell/kg, about 3X 10 6 Individual cells/kg, about 4X 10 6 Individual cells/kg, about 5X 10 6 Individual cells/kg, about 6X 10 6 Individual cells/kg, about 7X 10 6 Individual cells/kg, about 8X 10 6 Individual cells/kg, about 9X 10 6 Individual cells/kg, about 1X 10 7 Individual cells/kg, about 2X 10 7 Individual cells/kg, about 3X 10 7 Individual cells/kg, about 4X 10 7 Individual cells/kg, about 5X 10 7 Individual cells/kg, about 6X 10 7 Individual cells/kg, about 7X 10 7 Individual cells/kg, about 8X 10 7 Individual cells/kg, or about 9X 10 7 Individual cells/kg.
In some embodiments, the target dose of car+/CAR-t+/tcr+ cells is 1 x 10 6 -2×10 8 Individual cells/kg, e.g. 2X 10 6 In the range of individual cells/kg. It will be appreciated that administration above and below this range may be appropriate for certain subjects, and that appropriate administration levels may be determined by the health care provider as desired. In addition, multiple doses of cells may be provided according to the present disclosure.
In some aspects, the disclosure includes a pharmaceutical composition comprising at least one antigen binding domain as described herein and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition further comprises another active agent.
The CAR-expressing cell populations of the present disclosure can be administered alone or in a pharmaceutical composition in combination with a diluent and/or with other components (e.g., IL-2 or other cytokines or cell populations). The pharmaceutical compositions of the present disclosure may comprise a population of CAR-expressing or TCR-expressing cells, such as T cells described herein, in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents, or excipients. Such compositions may comprise buffers, such as neutral buffered saline, phosphate buffered saline, and the like; carbohydrates, such as glucose, mannose, sucrose or dextran, mannitol; a protein; polypeptides or amino acids, such as glycine; an antioxidant; chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and (3) a preservative. The compositions of the present disclosure are preferably formulated for intravenous administration.
The pharmaceutical composition (solution, suspension, etc.) may comprise one or more of the following: sterile diluents, such as water for injection, saline solution (preferably physiological saline), ringer's solution, isotonic sodium chloride; fixed oils such as synthetic mono-or diglycerides which can act as solvents or suspending media; polyethylene glycol, glycerol, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamine tetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for modulating tonicity, such as sodium chloride or dextrose. The parenteral formulation may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The injectable pharmaceutical composition is preferably sterile.
In some embodiments, an engineered immune cell that expresses any of the antigen-specific CARs described herein on the cell surface can reduce, kill, or lyse endogenous antigen-expressing cells of a patient when administered to the patient. In one embodiment, the percent reduction or lysis of cells of an endogenous cell or cell line expressing an antigen by an antigen of an engineered immune cell expressing an antigen of any of the antigen specific CARs described herein is at least about or greater than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%. In one embodiment, the percent reduction or lysis of cells of an endogenous antigen-expressing cell or antigen-expressing cell line produced by an engineered immune cell expressing an antigen-specific CAR is from about 5% to about 95%, from about 10% to about 90%, from about 10% to about 80%, from about 10% to about 70%, from about 10% to about 60%, from about 10% to about 50%, from about 10% to about 40%, from about 20% to about 90%, from about 20% to about 80%, from about 20% to about 70%, from about 20% to about 60%, from about 20% to about 50%, from about 25% to about 75%, or from about 25% to about 60%. In one embodiment, the cells that endogenously express the antigen are bone marrow cells endogenously expressing the antigen.
In one embodiment, the percent reduction or lysis of a target cell (e.g., an antigen-expressing cell line) produced by an engineered immune cell expressing an antigen-specific CAR of the present disclosure at a cell surface membrane can be measured using an assay disclosed herein.
The method may further comprise administering one or more chemotherapeutic agents. In certain embodiments, the chemotherapeutic agent is a lymphocyte depleting (pretreatment) chemotherapeutic agent. For example, a method of modulating a patient in need of T cell therapy comprising administering to the patient a prescribed beneficial amount of cyclophosphamide (at 200mg/m 2 Day and 2000mg/m 2 Between/day, about 100mg/m 2 Day and about 2000mg/m 2 Day/day; for example, about 100mg/m 2 Day, about 200mg/m 2 Day, about 300mg/m 2 Day, about 400mg/m 2 Day, about 500mg/m 2 Day, about 600mg/m 2 Day, about 700mg/m 2 Day, about 800mg/m 2 Day, about 900mg/m 2 Day, about 1000mg/m 2 Day, about 1500mg/m 2 Day or about 2000mg/m 2 Day) and the prescribed dose of fludarabine (at 20 mg/m) 2 Day and 900mg/m 2 Between/day, at about 10mg/m 2 Day and about 900mg/m 2 Between/days; for example, about 10mg/m 2 Day, about 20mg/m 2 Day, about 30mg/m 2 Day, about 40mg/m 2 Day, about 40mg/m 2 Day, about 50mg/m 2 Day, about 60mg/m 2 Day, about 70mg/m 2 Day, about 80mg/m 2 Day, about 90mg/m 2 Day, about 100mg/m 2 Day, about 500mg/m 2 Day or about 900mg/m 2 Day). A preferred dosing regimen involves treating a patient, comprising administering to the patient about 300mg/m daily prior to administering to the patient a therapeutically effective amount of the engineered T cells 2 Cyclophosphamide per day and about 30mg/m 2 Fludarabine/day for three days.
In some embodiments, lymphocyte depletion further comprises administration of a CD52 antibody. In some embodiments, the CD52 antibody is alemtuzumab. In some embodiments, the CD52 antibody is administered intravenously at a dose of about 13 mg/day.
In other embodiments, the antigen binding domain, transduced (or otherwise engineered) cells, and chemotherapeutic agent are each administered in an amount effective to treat the disease or condition in the subject.
In certain embodiments, compositions comprising the CAR-expressing immune effector cells disclosed herein can be administered with any number of chemotherapeutic agents that can be administered in any order. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and Cyclophosphamide (CYTOXAN) TM ) The method comprises the steps of carrying out a first treatment on the surface of the Alkyl sulfonates such as busulfan, imperosulfan (endoprostufan) and piposulfan (piposulfan); aziridines, such as benzodopa, carboquone, midadopa (metadopa) and You Liduo bar (urodopa); ethyleneimine and methyl melamine, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphamide, and trimethylol melamine; nitrogen mustards, such as chlorthalidomide, napthalazines, chlorophosphamide, estramustine, ifosfamide, mechlorethamine oxide hydrochloride, melphalan (melphalan), novobixing (novembichin), cholesterol-p-phenylacetic acid nitrogen mustards, prednisone nitrogen mustards, qu Luolin amine, uracil mustard; nitrosoureas such as carmustine (carmustine), chlorourectin, fotemustine (fotemustine), lomustine (lomustine), nimustine (nimustine), and ranimustine (ranimustine); antibiotics, e.g. aclacinomycin, radiomycin, oslarmycin, azaserine, bleomycin, actinomycin C, calicheamicin, carborubicin (carbicin), carminomycin, acidophilic, chromomycin, dactinomycin, daunomycin, ditobacin (detorubicin), 6-diazo-5-oxo-L-norleucine, doxorubicin (doxorubiin), epirubicin (epiubicin), epothilone (esoubicin), idamycin, doxorubicin, mitomycin, mycophenolic acid, nogamycin, olivomycin, pelomycin, prednisomycin, puromycin, quinamycin, rodubicin (rodorubicin), streptoamycin, streptozocin, desmocidin, desmocide Ribostamycin, ubenimex, zinostatin, levorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as dinotefuran, methotrexate, pterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamphetamine, thioguanine; pyrimidine analogs such as, for example, ambcitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, deoxyfluorouridine, enocitabine, fluorouridine, 5-FU; androgens, such as carbosterone, drotasone propionate, cyclothioandrostane, emasculan, and testosterone; anti-adrenal properties such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; acetoglucurolactone; aldehyde phosphoramide glycosides; aminolevulinic acid; amsacrine; a double Sita cloth; a specific group; idatroke; obtaining the fluvastatin; colchicine; deaquinone; ai Fumi octyl; irinotecan acetate; eggshell robust; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mo Pai dar alcohol; nylon Qu Ading; penstatin (pentastatin); phenylamet (phenylamet); pirarubicin (pirarubicin); podophylloic acid; 2-acetylhydrazine; procarbazine; Carrying out a process of preparing the raw materials; a sirzopyran; germanium spiroamine; tenuazonic acid; triiminoquinone; 2,2',2 "-trichlorotriethylamine; uratam; vindesine; dacarbazine; mannosamine; dibromomannitol; dibromodulcitol; pipobromine; metoclopramide; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxol-like compounds, e.g. paclitaxel (TAXOL) TM Bristol-meliss nyquist oncology (Bristol-Myers Squibb Oncology), priston, new jersey and docetaxel (doxetaxel)>Rhne-Poulenc Rorer, antony, france); chlorthalic acid; gemcitabine (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum;etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine (vinorelbine); novelline (naveldine); mitoxantrone; teniposide; daunomycin; aminopterin; hilded (xeloda); ibandronate; CPT-11; topoisomerase inhibitor RF S2000; difluoromethyl ornithine (DMFO); retinoic acid derivatives, e.g. Targretin TM (Bei Seluo tin) Panretin TM (Li Cuituo Ning); ONTAK (optical network Unit) TM (diniinterleukin); epothilones; capecitabine (capecitabine); and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are anti-hormonal agents, such as antiestrogens, including, for example, tamoxifen, raloxifene, aromatase inhibiting 4 (5) -imidazole, 4-hydroxy tamoxifen, trawoxifene, raloxifene hydrochloride, LY117018, onapristone, and toremifene (farston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprorelin, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Combinations of chemotherapeutic agents are also administered where appropriate, including but not limited to CHOP, i.e., cyclophosphamide +.>Doxorubicin (Doxorubicin), vincristine +.>And Prednisone (Prednisone).
In some embodiments, the chemotherapeutic agent is administered concurrently or within one week after administration of the engineered cell, polypeptide, or nucleic acid. In other embodiments, the chemotherapeutic agent is administered 1 to 4 weeks or 1 week to 1 month, 1 week to 2 months, 1 week to 3 months, 1 week to 6 months, 1 week to 9 months or 1 week to 12 months after administration of the engineered cell, polypeptide or nucleic acid. In other embodiments, the chemotherapeutic agent is administered at least 1 month prior to administration of the cell, polypeptide or nucleic acid. In some embodiments, the method further comprises administering two or more chemotherapeutic agents.
A variety of other therapeutic agents may be used in combination with the compositions described herein. For example, other therapeutic agents that may be useful include PD-1 inhibitors, such as nivolumabParbolizumab +>Palbociclib, pilidab and alemtuzumab ++>
Other therapeutic agents suitable for use in combination with the present disclosure include, but are not limited to: ibrutinibOffatuzumab->Rituximab->Bevacizumab->Trastuzumab->Enmetrastuzumab +.>Imatinib->Cetuximab (+)>Panitumumab)/(panitumumab)>Katuxostat, temozolomide, ofatuzumab, tositumomab, butuximab, alemtuzumab, gemtuzumab, erlotinib, gefitinib, vandetanib, afatinib, lapatinib, lenatinib, axitinib, ceritinib, pazopanib, sunitinib, sorafenib, tositub, letatinib, axitinib, ceridinib, lenvatinib, daenib, pazopanib, regorafenib, simansaminib, ranafatinib, sunitinib, tivalenib, tositub, vandetatinib Entrictinib, cabotinib, imatinib, dasatinib, nilotinib, ponatinib, radatinib, bosutinib, litatinib, ruxolitinib, parkatinib, cobratinib, sematinib, trametinib, bimatinib, ai Leti, ceritinib, crizotinib, aflibercept, adAN_SNatide, a deniinterleukin-toxin conjugate, mTOR inhibitors (such as everolimus and temsirolimus), hedgehog inhibitors (such as sornid gedy and vemoji), CDK inhibitors (such as CDK inhibitors (pamazelnib)).
In some embodiments, a composition comprising CAR-containing immune cells can be administered with a treatment regimen to prevent Cytokine Release Syndrome (CRS) or neurotoxicity. Treatment regimens for preventing Cytokine Release Syndrome (CRS) or neurotoxicity may include cold self-priming antibody (lenzilumab), tosilizumab (tocilizumab), atrial natriuretic peptide (atrial natriuretic peptide, ANP), anakinra, iNOS inhibitors (e.g., L-NIL or 1400W). In additional embodiments, a composition comprising CAR-containing immune cells can be administered with an anti-inflammatory agent. Anti-inflammatory agents or drugs include, but are not limited to, steroids and glucocorticoids including betamethasone, budesonide, dexamethasone, hydrocortisone acetate (hydrocortisone acetate), hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone; non-steroidal anti-inflammatory drugs (NSAIDS), bagsIncluding aspirin (aspirin), ibuprofen (ibuprofen), naproxen (naproxen), methotrexate (methotrexate), sulfasalazine (sulfasalazine), leflunomide (leflunomide), anti-TNF agents, cyclophosphamide and mycophenolate. Exemplary NSAIDs include ibuprofen (ibuprofen), naproxen (naproxen), naproxen sodium (naproxen sodium), cox-2 inhibitors, and sialates. Exemplary analgesics include acetaminophen, oxycodone, and tramadol of propoxyphene hydrochloride. Exemplary glucocorticoids include cortisone (cortisone), dexamethasone (dexamethasone), hydrocortisone, methylprednisolone, prednisolone (prednisolone), or prednisone (prednisone). Exemplary biological response modifiers include molecules directed to cell surface markers (e.g., CD4, CD5, etc.), cytokine inhibitors (e.g., TNF antagonists (e.g., etanercept) Adalimumab (adalimumab)>And infliximab (Infliximab)>) A chemokine inhibitor, and an adhesion molecule inhibitor. Biological response modifiers include monoclonal antibodies and recombinant forms of the molecules. Exemplary DMARDs include azathioprine, cyclophosphamide, cyclosporine, methotrexate, penicillamine, leflunomide, sulfasalazine, chloroquine, gold (Gold) (oral (auranofin)) and intramuscular), and minocycline (minocycline).
In certain embodiments, the compositions described herein are administered in combination with a cytokine. Examples of cytokines are lymphokines, monokines and traditional polypeptide hormones. Among the cytokines are growth hormones such as human growth hormone, N-methionyl human growth hormone and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; a relaxin source; glycoprotein hormones such as Follicle Stimulating Hormone (FSH), thyroid Stimulating Hormone (TSH) and Luteinizing Hormone (LH); liver growth factor (HGF); fibroblast Growth Factor (FGF); prolactin; placental lactogen; miaole (mullerian) inhibitors; a mouse gonadotrophin-related peptide; inhibin; activin; vascular endothelial growth factor; an integrin; thrombopoietin (TPO); nerve Growth Factor (NGF), such as NGF- β; platelet growth factors; transforming Growth Factors (TGFs), such as TGF- α and TGF- β; insulin-like growth factors-I and II; erythropoietin (EPO); an osteoinductive factor; interferons, such as interferon- α, β, and γ; colony Stimulating Factors (CSFs), such as macrophage-CSF (M-CSF), granulocyte-macrophage-CSF (GM-CSF), and granulocyte-CSF (G-CSF); interleukins (IL), such as IL-1, IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15, IL-21; tumor necrosis factors, such as TNF- α or TNF- β; and other polypeptide factors, including LIF and Kit Ligand (KL). As used herein, the term cytokine includes proteins from natural sources or from recombinant cell cultures, as well as biologically active equivalents of the native sequence cytokines.
7. Kit and article of manufacture
The present disclosure provides kits comprising reagents for analyzing CAR T drugs according to the methods described herein. In some embodiments, the kit includes one or more reagents for detecting CD3 and tcrγδ (e.g., anti-CD 3 antibodies and anti-tcrγδ antibodies). In some embodiments, the kit further comprises one or more reagents for detecting CD45, CD5, CD52, CD107a, and/or CAR. In some embodiments, the kit further comprises one or more reagents for detecting tcrαβ. In some embodiments, the kit comprises one or more reagents for analyzing the CAR T drug according to the methods described herein, wherein the one or more reagents are conjugated to a detection label.
The present disclosure also provides kits comprising any of the cultured immune cells or engineered immune cells described herein, as well as pharmaceutical compositions thereof. In some exemplary embodiments, the kits of the present disclosure include allogeneic CAR T cells for administration to a subject.
The application also provides an article of manufacture comprising any of the therapeutic compositions or kits described herein. Examples of articles include vials (e.g., sealed vials).
The following examples are for illustrative purposes only. Indeed, various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art from the foregoing description.
Examples
Allogeneic CAR T cell production
CAR T cells were prepared from healthy donor leukocyte isolates, a process involving transduction of lentiviruses with CAR scFv transgenes that recognize CD 19. The leukocyte separation fluid from the apheresis procedure was washed using a Sepax cell separation system to remove platelets and RBCs were removed by Ficoll purification. Then using TransAct TM Activator (MACS GMP T cell TransAct) TM ) To inoculate and activate cells to induce activation and proliferation of T cells. Cells were then plated in six well plates, where LVV contained a construct expressing CD19 (4G 7) scFv/4-1BB/CD3 ζcar. Then, agilePolse is used TM MTX System Using Electroporation (EP)mRNA was transfected into T cells to genetically disrupt TRAC and CD52 genes and TCR αβ and CD52 protein expression. After expansion, CAR T cells were harvested and TCR αβ+ cell depleted to reduce the remaining TCR αβ+ cells to a minimum level. CliniMACS Prodigy is capable of automated and blocking processing, selected for TCR αβ+ cell rejection. CAR T cells harvested from the bioreactor were subjected to cell enrichment, antibody labeling and depletion on Prodigy using Miltenyi CliniMACS TCR a/β kit (anti-TCR a β antibody clone BW 242/412). CD19 specific CAR T cells Allo-501 and Allo-501A were tested. Both types of CAR T cells expressed the same anti-CD 19 scFv (based on clone 4G 7); allo-501 CAR T cells also express rituximab mimotopes on the cell surface, whereas Allo-501A CAR T cells do not express rituximab mimotopes.
Cell culture
Daudi cells (CD 19 positive target tumor cells) and KG1a cells (CD 19 negative control cells) were obtained from the American type culture Collection (VA, USA) and maintained in complete medium consisting of Roswell Park Memorial Institute (RPMI) medium or Dulbecco's Modified Eagle's Medium (DMEM)Life Technologies, NY, USA) containing 10% heat inactivated fetal bovine serum (Gibco) and additives (2 mM glutamine, gibco), 0.1mM nonessential amino acids (Gibco), 100 μg/mL streptomycin (Sigma-Aldrich, MO, USA) and gentamicin (10 μg/mL) (Sigma-Aldrich) were incubated in a humidified incubator at 37℃and 5% CO 2.
Flow cytometry
CD19 CAR expression was assessed by intracellular staining using an anti-idiotype antibody that recognizes scFv Fab. The anti-idiotype antibody may be an antibody as described in, for example, WO 2020/214937. To investigate the multifunctional capacity of CAR T cells upon target stimulation, intracellular cytokine staining was performed. After co-culture of Daudi cells (CD 19 positive) or KG1a cells (CD 19 negative) with fluorescent-labeled anti-human CD107a antibodies, allogeneic CD19 CAR T cells were stained using a 15-color flow cell group against immune cell lineages present in PBMCs (table 1). CD19 allogeneic CAR T cells are also incubated under pan T cell stimulation conditions, e.g., in the presence of PMA (phorbol myristate acetate) and ionomycin (calcium ionophore) but in the absence of target cells as positive controls. During co-cultivation, anti-human CD107a-BV421, monensin A (protein transport inhibitor, BD Biosciences) and Golgi Plug were grown TM (Pharmingen) was added to the co-culture wells and incubated with target cells for 6 hours or 18 hours. Cells were then harvested and blocked with human IgG to remove non-specific binding, followed by staining with surface antibodies. After incubation and washing, the incubation and washing were carried out first with Cytofix/Cytoperm TM (Becton Dickinson) cells were fixed and permeabilized, then blocked with human IgG (Sigma), then with cellsThe inner cytokine stained cells and the cells were analyzed on BD Fortessa X-20 using FacsDIVA software. Cell viability was determined by staining with Fixable far red dye (Invitrogen, CA, USA). The lineage degranulation flow cytometry analysis panel is shown in table 1, which shows exemplary suitable detection reagents. All antibodies were obtained from Biolegend or BD Biosciences except for anti-tcrαβ (Miltenyi Biotech) and anti-idiotype (Allogene) antibodies. The running fcs file was compensated and manually gated using the FlowJo of Treestar. Boolean gating of mutually exclusive cytokine-positive populations (ifnγ, tnfα and IL 2) assessed the versatility of CD107a positive and negative populations, respectively.
TABLE 1
Statistics
At least 5 attributes (CD 107a, CD19 CAR, tnfa, IL2 and ifnγ) of the samples were analyzed using Pearson correlation coefficient analysis on Spotfire (Tibco), and regression analysis was performed on the samples.
Example 1 TCRαβ+ count based on internal biological control
The allogeneic CAR T cell products described above have been subjected toThe ablated TRAC locus is edited by a gene that minimizes the risk of GvHD (graft versus host disease), which may be caused by the donor TCR recognizing host cell antigens as foreign. After CAR transduction and genetic modification, the remaining tcrαβ+ donor CAR T cells are removed by anti-tcrαβ antibody mediated depletion. After depletion, the number of tcrαβ+ CAR T cells remaining is typically measured directly by immunoassay (e.g., flow cytometry). If possible, compatible antibodies that bind to epitopes different from the antibodies used for the knockout are selected for detection. Reagent incompatibility can lead to inaccurate results. Furthermore, by flow cytometryThe exact direct measurement of (a) depends on the appropriate gating settings, i.e. the appropriate tcrαβ+ cutoff from donor matched T cells is set. This experiment was aimed at studying whether the remaining tcrαβ+ could be counted according to an internal biological control rather than a direct measurement.
Flow cytometric analysis was performed using a mixture of detection reagents specific for T cell lineage markers: such as CD3, CD4, CD5, CD8, tcrαβ and tcrγδ.
The remaining tcrαβ+ cells were first analyzed by flow cytometry with designated gating. As shown in fig. 1 and table 2, different readings were generated based on different gating settings of different donors. Thus, due to the lack of reliable universal gating on all donor samples, accurate determination of the remaining tcrαβ+ T cells in each batch of allogeneic CAR T cell preparations must rely on donor-specific gating control. Donor-specific gating control requires that unmodified donor cell samples be reserved prior to the preparation process to determine the tcrαβ cutoff of the donor-matched drug. This additional consideration further complicates the preparation process.
TABLE 2
To bypass this problem, the remaining tcrαβ+ cells were next determined by using internal biological controls. CD3 staining is commonly used as an indicator of T cells. During gene ablation of TRAC, the protein complex of the CD 3T cell co-receptor is unstable on the cell surface and is no longer available for extracellular surface detection. We hypothesize that we can evaluate intracellular CD3 on TRAC ablated T cells, as well as CD5 co-expressed with intracellular CD3 expression. We first tested whether CD5 could be used as another T cell antigen that is detectable and does not destabilize on the cell surface upon disruption of the TRAC gene.
Two flow-through sets were performed using a primary flow cytometry mixture comprising the following T cell lineage markers, one stained with intracellular CD3 and the other with surface staining: CD4, CD8, CD5. Flow cytometric analysis was performed by manually gating T cell populations with gating logic applied in parallel samples to assess the total number of live cd5+ events of intracellular cd3+, and vice versa.
As shown in fig. 2A, based on gating of the population of live T cells, we demonstrate that extracellular CD3 is lost upon TRAC ablation in the allogeneic CAR T cell product. We observed a correlation of extracellular CD5 with intracellular CD3 in the TRAC ablated allogeneic CAR T cell product, with a population of 95.7% intracellular cd3+ showing 93.3% surface cd5+ positives. In addition, 94.2% of intracellular cd3+ is surface cd5+, and 96.7% is the opposite. Finally, 89.7% of all living cells were double positive for surface cd5+ and intracellular cd3+. See fig. 2B. The data are summarized in table 3. Thus, it is feasible to use another surface expression marker CD5 as an indicator of T cells (e.g., TRAC ablated allogeneic CAR T cells).
TABLE 3 Table 3
Then, figure 3 depicts the process of determining the remaining tcrαβ+ T cells after transduction of the CAR and gene ablation of the TRAC, and in this case, knockout of the CD52 gene. Panels a and B show the separation of cells of interest according to size and particle size. Viable cd45+ T cells were isolated for further characterization (panel C) and analyzed for surface expression of CD3 and CD5 (panel D). The cells were further analyzed for TCR αβ expression using an anti-TCR αβ detection antibody (same as the antibody used for the knockout, i.e., clone BW 242/412) (panel E). The remaining tcrαβ+ T cells were determined to be 1.23% by direct measurement (panel E). Meanwhile, cells were analyzed for TCR γδ expression for CD3 extracellular staining. The results in panel F show that 92.2% of the total cells are CD 3-and TCRγδ -, and the remaining 7.78% are surface CD3+ and TCRγδ+. By further analysis, the surface cd3+ cells (7.48%) of panel D were all tcrγδ+ (99.6% in panel G), with the remaining surface cd3+ cells accounting for 0.35%, representing the remaining tcrαβ+ T cells.
The results show that the level of residual tcrαβ+ cells (1.23%) determined by direct detection is overestimated compared to the assay (0.35%) performed by using internal biological controls. Table 4 shows the analytical summary of the comparison of the two methods for three samples of CAR T cells derived from two donors and the error range between the two methods.
TABLE 4 Table 4
Example 2 increased surface expression of degranulation marker CD107a was associated with CAR T cells with enhanced versatility
We next began to investigate whether the target-specific induction of CD107a was correlated with the extent of effector cytokine induction in defined immune cell subsets. The present experiment was aimed at studying whether induction of surface CD107 was associated with an increase in effector cytokines and an increase in killing of CAR T cells.
CD19 CAR T cells were co-cultured with cd19+ or CD 19-target cells for 6 hours as described above. The results in fig. 4 show that for target-specific stimulation of cd19+daudi cells, the CAR expression levels determined by intracellular staining showed the highest correlation with tnfα (Pearson r=0.79, regression rζ2=0.631, p < 0.02), but no correlation with any other effector molecules tested (CD 107a, ifnγ, IL 2) in the various immune cell subsets. When the correlation was studied in a T cell memory map, the results showed that the relationship was less robust (data not shown). The highest immune lineages for CAR cd19+ and CD107a were the remaining tcrαβ+ cells (< 0.5% of drug after TRAC TALEN mediated ablation) (80.6% car+,64.8% CD107 a+), cd8+ T cells (72.0% car+,44.6% CD107 a+), and NKT cells (65.4% car+,48.6% CD107 a+). We also observed that the immune cell lineage with the lowest level of CD107a induction was cd4+ T cells (81.7% car+,30.4% CD107 a+) despite the high level of CAR expression. Notably, CD107a was not induced when CAR T cells were co-cultured with off-target tumor cells, especially in the tcrαβ+ lineage, suggesting that this remaining population did not produce off-target allograft versus host effect (GvH). For pan CAR T cell-specific stimulation with PMA and ionomycin, IL-2 was significantly correlated with CAR expression (r=0.92, p < 0.0005), followed by tnfα, which was driven predominantly by the cd4+ population (r=0.77, p < 0.02). In addition, the same trend specific for IL-2 was observed in the T cell memory population (data not shown).
In summary, in immune cell lineages, CAR expression levels (% car+) were significantly correlated with tnfα expression levels, but not with ifnγ or IL2, CD107a induction was highest in tcrαβ+, cd8+ and NKT cells. These results underscore the correlation represented by the high correlation of CD107a as a cytokine-induced allogeneic CAR T drug in different immune cell lineages that respond to target cells. It also avoids the need to perform intracellular cytokine staining, which is not possible in GMP environments. Furthermore, the discovery that CD107a can be used as a representative of high correlation also improves the current method of measuring single cytokines directly by ELISA (enzyme linked immunosorbent assay). Such direct measurement cannot indicate which cell subsets in the drug are capable of secreting cytokines.
Although we observed no significant correlation between CAR positivity and CD107a intracellular staining in Daudi co-cultured CAR T cells, CD107a expression levels showed robust correlation with all three cytokines: in CAR T cells co-cultured with Daudi cells, ifnγ (r=0.91, p<0.0001)、TNFα(r=0.66,p<0.01 And IL2 (Pearson r=0.8, rζ2=0.646, p) <0.01). See fig. 5A and 5D. As shown in fig. 5C, the majority of positive CD107a staining was consistent with positive CAR staining in all CAR T cells stimulated with tumor cells (see bottom right-most panel of fig. 5C). The highest immune lineage induced by CD107a was the remaining tcrαβ+ cells (in TRACMediated post-ablation drug administration<0.5%) (64.8% cd107a+,50.9% ifnγ+,50% tnfa+, 13.9% il2+). The other immune lineages most induced by CD107a were NKT cells (48.6% cd107a+,24.8% ifnγ+,28.3% tnfα+,1.07% il2+) and cd8+ T cells (44.6% cd107a+,16.7% ifnγ+,21.5% tnfα+,0.69% il2+). The immune cell lineage with the lowest level of CD107a induction was tcrγδ T cells (23.2% CD107 a+), which also indicated the number of car+ staining (24.9% car+) and minimal cytokine positive events (7.46% ifnγ,12.9% tnfα+,0.23% IL 2). NK cells (CD 5-cd56+) also showed similar low levels of CD107a induction and CAR expression (32.45% CD107a+,14.41% car+). For pan CAR T cell-specific stimulation with PMA and ionomycin, the correlation of CD107a with any of the cytokines in the entire lineage subpopulation was lower than the robust correlation observed by Daudi cd19+ specific stimulation. The results indicate that CD107a is specifically induced upon antigen-specific recognition.
In summary, the results show that CD107a is closely related to the extent of induction of all three cytokines (ifnγ, tnfα and IL 2), far exceeding the extent of CD19 CAR expression, which can be attributed to the different car+% in the different cell lineages, as shown in fig. 4.
In CD19 CAR T cells (ALLO-501A) and CAR T cells specific for non-CD 19 target B (CAR B), the correlation between surface CD107a and multiple effector cytokines, i.e., versatility, was assessed by simple linear regression. After 6 hours co-culture with cells expressing the respective targets (Daudi, ACHN-GFP or Raji cells) and target negative control cells, a correlation between the surface expression of CD107a and the versatility of CAR T cells was observed. The versatility is demonstrated by intracellular staining of two or three of the three cytokines tnfα, IL2 and infγ in CAR T cells. The correlation strength of the simple linear regression analysis was determined as follows: r=0.00-0.19, no correlation/very weak correlation; r=0.20-0.39, weak correlation; r=0.40-0.59, medium correlation; r=0.60-0.79, strong correlation; r=0.80-1.00, a strong correlation. As shown in fig. 7A-7B, when three or two cytokines were studied, a strong correlation was observed for CD19 CAR T cells (three cytokines r= 0.6223, two cytokines r= 0.7740) and this correlation was statistically significant for both cytokine data (p=0.0242). When two cytokines were studied, a strong correlation was also observed in CAR B T cells (r= 0.6785), although the data was not statistically significant. When three cytokines were studied, a weak correlation of CAR B T cells was observed (r= 0.3761). When the cells were co-cultured for 18 hours, no correlation or weak correlation was observed (data not shown).
We then studied the ability of Daudi co-cultured cd107a+ cells or CD 107-cells to express each of the three cytokines ifnγ, IL2 and tnfα, alone or in two or more, in each cd19 car+ immune cell lineage. As shown in fig. 6, cells expressing only ifγ (i.e., ifng+il2-tnfα -) are cd107a+ enriched compared to the CD107 a-population among the total events, T cells, cd8+ T cells, tcrγδ T cells, NKT cells, tcrαβ+ and NK cells of almost all car+ lineage metrics. Except for CAR19+cd4+ T cells. See fig. 6. Of the total events, T cells, cd8+ T cells, tcrγδ T cells, NKT cells, tcrαβ+ and NK cells, cells expressing tnfα alone (i.e., ifnγ -IL2-tnfα+) also showed an abundance of cd107a+ compared to the CD107 a-population, measured by nearly all of the CAR19+ lineage. Except for the remaining tcrαβ+ T cells. Most notably, cells expressing a combination of two or more of ifnγ, IL2 and tnfα were significantly enriched for CD107a cells in the entire car+ subpopulation.
In summary, CD107a expression defines target-specific induction of a combination of two or more of ifnγ, IL2, and tnfα in all car+ immune subpopulations measured, and CD107a surface expression can be used as an indicator of the versatility of allogeneic CAR T cells. See figure 3 panel I for analysis from the "AS" population of panel E ("active agent", defined AS live car+/tcrαβ -T cells for regulatory purposes). Because of the limited sample size, no statistics were performed in this study, although CAR T cells derived from matched donor cells with Allo-501 or Allo-501A showed similar cytokine induction patterns in the CD107a population. Thus, there is a correlation between cd107a+ in car+ cells and effector cytokine induction. This observation further demonstrates that surface CD107a can be used as an indicator of the versatility of CAR T cells.
To evaluate unbiased clustering of effector molecules based on the expression profile of lineage markers, t-distribution random neighborhood embedding (t-SNE) analysis and FlowSOM (self-organizing map clustering algorithm) were performed on downsampled viable single cell cd5+, cd45+ populations. We found that CD107a specifically defined cell clusters that were multifunctional for the combination of expressed cytokines (ifnγ+, il2+ and tnfα+) using an unsupervised clustering method (data not shown).
In summary, the results presented indicate that degranulation marker CD107 can be indicative of target antigen-specific induction of cytokines and thus can be representative of efficacy assessment of allogeneic CAR T cells. Surface expression of CD107 at degranulation is a more readily available biomarker whose detection bypasses the cumbersome steps of direct measurement of intracellular staining of each induced cytokine, which are often difficult to implement in a large scale manufacturing environment.
Sequence listing
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Claims (35)
1. A method of analyzing an immune cell population, wherein the immune cell population has been engineered to introduce one or more genetic modifications at the tcra and/or tcrp loci that reduce or impair tcra surface expression, the method comprising the steps of:
a) Obtaining or measuring viable cd45+ cells from the population of immune cells;
b) Obtaining or measuring cd5+/cd3+ cells from the cells described in step a); and
c) Measuring or determining the percentage or number of CD3+/TCRγδ -cells from the cells described in step b),
wherein the percentage or number of cd3+/tcrγδ -cells in step c) represents the percentage or number of tcrαβ+ T cells present in the immune cell population.
2. A method of measuring the percentage or number of tcrαβ+ T cells in an immune cell population, wherein the immune cell population has been engineered to introduce one or more genetic modifications at the tcrαand/or tcrβ loci that reduce or impair tcrαβ surface expression, the method comprising the steps of:
a) Obtaining or measuring viable cd45+ cells from the population of immune cells;
b) Obtaining or measuring cd5+/cd3+ cells from the cells described in step a); and
c) Measuring or determining the percentage or number of CD3+/TCRγδ -cells from the cells described in step b),
wherein the percentage or number of cd3+/tcrγδ -cells in step c) represents the percentage or number of tcrαβ+ T cells in the immune cell population.
3. The method of claim 1 or claim 2, wherein the population of immune cells has been engineered to express a Chimeric Antigen Receptor (CAR).
4. The method of any one of the preceding claims, wherein the population of immune cells is a population of Peripheral Blood Mononuclear Cells (PBMCs) or cd4+ and/or cd8+ T cells.
5. The method of any one of the preceding claims, wherein the percentage or number of tcrαβ+ T cells is determined by subtracting the percentage or number of cd3+/tcrγδ+ cells from the population of cd5+/cd3+ cells described in step b).
6. A method of analyzing a population of immune cells that has been engineered to express a CAR, the method comprising the step of measuring surface CD107 of the CAR T cells after antigen stimulation, wherein an increased level of surface CD107 compared to the level prior to antigen stimulation is indicative of a multifunctional CAR T cell.
7. The method of claim 6, wherein the increase in the level of surface CD107 is a percentage increase or an average/median fluorescence intensity increase of surface CD 107.
8. The method of claim 6 or claim 7, wherein the multi-functional CAR T cell secretes a higher level of tnfα after antigen stimulation than a non-multi-functional CAR T cell.
9. The method of any one of claims 6 to 8, wherein the CAR T cell has been engineered to introduce one or more genetic modifications at the tcra and/or tcrp loci that reduce or impair tcra surface expression.
10. The method of any one of claims 6 to 9, further comprising measuring one or more cytokines selected from the group consisting of: INFγ, TNF α, IL2, GM-CSF, CXCL1, IL-1B, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-17, IL-21, IL-22, IL-23, CXCL11, mip1a, mip1B, mip3a, TNFb, perforin, granzyme A, granzyme B, granzyme H, CCL, IP-10, CCL5, TGFb, sCD137, sCD40L, MCP-1 and MCP-4.
11. The method of any one of claims 6 to 10, wherein the CAR T cells are stimulated by co-culturing the CAR T cells with target cells that express an antigen of the CAR.
12. The method of claim 11, wherein the target cell is a tumor cell.
13. The method of any one of claims 6 to 12, wherein the level of surface CD107 is measured by flow cytometry.
14. The method of any one of claims 6 to 13, wherein CD107 is CD107a and/or CD107b.
15. The method of any one of claims 6 to 14, wherein CD107 is measured about 6 hours after antigen activation.
16. A method of analyzing an immune cell population, wherein the immune cell population has been engineered to introduce one or more genetic modifications at a TCR a and/or TCR β locus that reduce or impair TCR a β surface expression, and wherein the lymphocyte population has been engineered to express a Chimeric Antigen Receptor (CAR), the method comprising the steps of:
a) The method of claim 1 or claim 2, measuring or determining the percentage or number of tcrαβ+ T cells in the population of immune cells; and
b) Measurement in the immune cell population:
i) Percentage or number of car+ T cells; and/or
j) Surface CD107 levels after antigen stimulation.
17. The method of claim 16, wherein an increase in the level of surface CD107 after antigen stimulation compared to the level prior to antigen stimulation is indicative of a multi-functional CAR T cell.
18. The method of claim 17, wherein the increase in the level of surface CD107 is a percentage increase or an average/median fluorescence intensity increase of surface CD 107.
19. The method of any one of claims 16 to 18, wherein CD107 is CD107a and/or CD107b.
20. The method of any one of claims 16 to 19, wherein the percentage or number of car+ T cells is measured using an anti-idiotype antibody.
21. The method of any one of claims 16 to 20, wherein CD107 is measured about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours after antigen activation.
22. The method of any one of the preceding claims, wherein the population of immune cells is PBMC or a population of cd4+ and/or cd8+ T cells.
23. The method of any one of the preceding claims, wherein the percentage or amount is measured by flow cytometry.
24. The method of any one of the preceding claims, wherein the population of immune cells is obtained from a healthy donor.
25. The method of any one of the preceding claims, wherein the CAR T cells are allogeneic CAR T cells.
26. The method of any one of the preceding claims, wherein the immune cell expresses a CD19 CAR.
27. The method of any one of the preceding claims, further comprising the step of filling the population of immune cells into one or more containers, provided that the number or percentage of tcrαβ+ T cells does not exceed a predetermined threshold and/or if the population of immune cells comprises a multifunctional CAR T cell.
28. A method of preparing a pharmaceutical product comprising an engineered immune cell, the method comprising the method of any one of the preceding claims.
29. A kit or article of manufacture for analyzing CAR T cells, the kit or article of manufacture comprising one or more reagents for detecting CD3 and tcrγδ.
30. The kit or article of manufacture of claim 29, further comprising one or more reagents for detecting CD45, CD5, CD52, CD107a and/or CAR.
31. The kit or article of manufacture of claim 29 or claim 30, wherein the one or more reagents comprise an antibody.
32. The kit or article of manufacture of any one of claims 29 to 31, wherein the one or more reagents are conjugated to a detectable label.
33. The kit or article of manufacture of claim 32, wherein the detectable label is selected from the group consisting of: fluorescent labels, photochromic compounds, protein fluorescent labels, magnetic labels, radioactive labels and haptens.
34. The kit or article of manufacture of claim 33, wherein the fluorescent label is selected from the group consisting of: atto dye, alexafluor dye, quantum dot, hydroxycoumarin, aminocoumarin, methoxycoumarin, cascade blue, pacific orange, luciferin yellow, NBD, R-Phycoerythrin (PE), PE-Cy5 conjugate, PE-Cy7 conjugate, red 613, perCP, truRed, fluorX, fluorescein, BODIPY-FL, cy2, cy3B, cy3.5, cy5, cy5.5, cy7, TRITC, X-rhodamine, lissamine rhodamine B, texas Red, allophycocyanin (APC), APC-Cy7 conjugate, indo-1, fluo-3, fluo-4, DCFH, DHR, SNARF, GFP (Y66H mutation), GFP (Y66F mutation), EBFP2, blue copper mine, GFPuv T-Barbamate, azure, mCFP, mTurquoise2, ECFP, cyPet, GFP (Y66W mutation), mKeima-Red, tagCFP, amCyan1, mTTP 1, GFP (S65A mutation), mi Duli assortment of green, wild-type GFP, GFP (S65C mutation), turboGFP, tagGFP, GFP (S65L mutation), emerald, GFP (S65T mutation), EGFP, allevame green, zsGreen1, tagYFP, EYFP, topaz, venus, mCitrine, YPet, turboYFP, zsYellow1, kusapara orange, mOrange, allophycocyanin (APC), mKO, turboRFP, tdTomato, tagRFP, dsRed monomer, dsRed2 ("RFP"), mStrawberry, turboFP, asRed2, mRFP1, J-Red, R-phycoerythrin (RPE), B-phycoerythrin (BPE), mCherry, hcRed1, katusha, P3, polymethylphycocyanin (PerCP), mKate (TagFP 635), turboFP635, mPLbin and mRaspberry.
35. The kit or article of manufacture of any one of claims 29 to 34, wherein the one or more reagents are used in flow cytometry.
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US63/125149 | 2020-12-14 | ||
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US63/265086 | 2021-12-07 | ||
PCT/US2021/063245 WO2022132720A1 (en) | 2020-12-14 | 2021-12-14 | Methods and reagents for characterizing car t cells for therapies |
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