WO2005092371A1 - Vaccin a cellule hybride - Google Patents

Vaccin a cellule hybride Download PDF

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Publication number
WO2005092371A1
WO2005092371A1 PCT/GB2005/050032 GB2005050032W WO2005092371A1 WO 2005092371 A1 WO2005092371 A1 WO 2005092371A1 GB 2005050032 W GB2005050032 W GB 2005050032W WO 2005092371 A1 WO2005092371 A1 WO 2005092371A1
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WIPO (PCT)
Prior art keywords
cell
cells
hybrid
tumour
lymphoblastoid
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PCT/GB2005/050032
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English (en)
Inventor
Michael John Browning
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University Of Leicester
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/10—Cells modified by introduction of foreign genetic material
    • C12N5/12—Fused cells, e.g. hybridomas
    • C12N5/16—Animal cells
    • C12N5/163—Animal cells one of the fusion partners being a B or a T lymphocyte
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5152—Tumor cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/80—Vaccine for a specifically defined cancer

Definitions

  • the present invention relates to a vaccine for the treatment and/or prevention of cancer.
  • the invention relates to a hybrid cell vaccine for the treatment of cancer.
  • Further aspects of the invention relate to hybrid cells for use in such vaccines, to methods of producing such vaccines and cells, and to additional uses for such cells.
  • One such approach is the stimulation of the patient's own immune system to attack cancerous cells.
  • Such stimulation may be achieved by means of cellular vaccines; that is, by the administration of cells to a patient which will stimulate the immune system such that it recognises and attacks cancerous cells.
  • This may be achieved through the use of cells which express similar or identical antigens to in vivo cancer cells.
  • One promising approach is the use of hybrid cell vaccines, with the cells being derived from a fusion of a professional antigen presenting cell, such as dendritic cells, with a tumour cell.
  • the fused cell presents antigens derived from the tumour cell to the patient's immune system, thereby stimulating recognition and attack of the in vivo tumour.
  • the aim of these approaches is essentially to make the tumour cell resemble professional antigen presenting cells in the induction of the primary tumour specific T-cell responses.
  • Hybrid cell vaccines are generally derived from antigen presenting cells fused with tumour cell lines.
  • the cell line may have undergone some mutation or modification which may disrupt or alter the antigens presented by the tumour cell line, so reducing the effectiveness of the vaccine. This unpredictable variation in vaccine composition is undesirable. Further undesirable variation in vaccine composition arises from the use of dendritic cells as the antigen presenting cell.
  • Such cells may be difficult to maintain in culture after fusion, and may be difficult to characterise, both of which features could reduce the efficacy of vaccines derived therefrom. Further, it is believed that fusions of dendritic cells may be unstable, and that vaccines derived from such fusions may include non-fused dendritic cells, or cells simply transformed with tumour antigens. This unpredictability could lead to a reduction in vaccine efficacy or use on patients for whom it is not appropriate. There is a need for an alternative source of hybrid cell vaccines.
  • a method of producing a vaccine for use in the treatment and/or prevention of cancer comprising: obtaining at least one tumour cell ex vivo, and fusing the tumour cell with at least one lymphoblastoid cell, to provide at least one hybrid cell.
  • the present invention therefore allows for a cellular vaccine to be generated from ex vivo tumour cells.
  • ex vivo is meant tumour cells obtained directly from a patient, rather than cells which have been cultured to provide an in vitro cell line; such cells may also be known as primary cells.
  • ex vivo cells are less likely to have undergone modification or mutation (other than those leading to the cancerous condition) than tumour cell lines.
  • the use of ex vivo cells also permits the generation of fusion cell lines derived from a specific tumour type, without being limited to those tumour types from which cell lines have previously been derived. This allows for a wider range of possible vaccine targets than with prior art methods.
  • the use of lymphoblastoid cells as antigen presenting cells has a number of advantages over the use of dendritic cells; for example, stability of fusions and ease of post-fusion cultivation, cloning, and characterisation. This allows for a greater consistency in vaccine composition, and for more stable vaccines.
  • the lymphoblastoid cell is a B lymphoblastoid cell.
  • the lymphoblastoid cell is preferably activated; activation increases the expression of a range of molecules, such as MHC and cost ⁇ muiatory ligands such as CD80 and CD86 which enhance the cell's function as a professional antigen presenting cell and improve immunogenicity.
  • the lymphoblastoid cell may conveniently be activated with a virus, preferably with Epstein-Ban- Virus.
  • the method may also comprise the step of generating activated lymphoblastoid cells. Suitable protocols for generating such activated cells are known in the art.
  • EBV latency of the lymphoblastoid cell may also affect the immunogenicity of the hybrid cell; for this reason, it is preferred that EBV latency type III lymphoblastoid cells (Ke ⁇ et al. Virology 1992; 187: 189-201) are used, since we believe these are more immunogenic than other latency types. However, other latency types may be used if desired.
  • An alternative method of activation which may be used is activation by CD40 ligation. Fusion of cells may be achieved by any convenient method. Polyethylene glycol (PEG), or PEG and DMSO (dimethyl sulphoxide) is preferred, but any suitable method may be used, for example electrofusion. virally-derived usogenic peptides, and so forth.
  • the vaccine may be autologous (that is, both tumour cells and antigen presenting cells are derived from the individual on whom the vaccine is to be used), semi-autologous (one type of cell, preferably the tumour cell, is derived from the individual on whom the vaccine is to be used), or allogeneic (neither cell type is derived from the individual on whom the vaccine is to be used). Allogeneic and semi- autologous vaccines, with antigen presenting cells derived from a different individual from that on whom the vaccine is to be used, can in certain circumstances have an adjuvant effect of allogeneic MHC expression obtained from the antigen presenting cells * This may improve the performance of such vaccines.
  • the method may further comprise the step of selecting hybrid cells. Selection may be achieved by any convenient method; for example, using selectable markers introduced into the antigen presenting cells, double-dye selection, chemical resistance or sensitivity of hybrid cells, and the like.
  • the method may further comprise the step of culturi ⁇ g hybrid cells.
  • Hybrid cells may be propagated in culture, and may conveniently be maintained under the same selection means as used to select hybrid cells. Hybrid cells may be cultured clonally, such that a cell line is obtained which is derived from a single hybrid cell. This allows for uniformity of cells within a single line, and for accurate characterisation of cells within the vaccine.
  • the hybrid cells, and / or the lymphoblastoid cells may be further modified.
  • Modifications may include transfection of cytokine genes (e.g., GM-CSF), genes to further enhance immunogenicity (for example, other costimulatory molecules not expressed), or specific tumour antigens; or may include knocking out particular genes, for example immunoglobulin genes of the parent lymphoblastoid cell so that only the tumour idiotype is expressed.
  • the method may further comprise the step of combining hybrid cells derived from two or more different hybrid cell clones. This allows for the possibility of some variation in cell lines within the vaccine, which may improve performance by for example allowing complementation of different characteristics of different cell lines.
  • the method may comprise the step of combining hybrid cells derived from two or more different fusion events.
  • the tumour cell may be obtained from any type of malignancy. Haematological malignancies are preferred; for example, leukaemias, lymphomas, and the like; although solid tumours may be used in certain embodiments.
  • the method may further comprise the step of characterising the hybrid cells; the self-propagating nature of hybrids derived from lymphoblastoid cells, plus the potential for cloning, means that the hybrid cells lend themselves to accurate characterisation, which is of benefit to the targeted use of the vaccine on particular tumour types.
  • Hybrid cells may be characterised by genetic / genomic, proteomic, and other means.
  • hybrid cells may be characterised to determine cell surface and intracellular protein expression (for example, cell surface molecules, T cell costimulatory ligand molecules); HLA (antigen presenting molecules) by genetic or protein expression methods; expression of known tumour antigens (e.g. MAGE family, fusion proteins from gene translocations e.g. bcr/abl, immunoglobulm idiotype, etc); characterisation of antigen processing pathways; responses to cytokines and other biochemical / biological stimuli; ability of hybrid cells to stimulate T cell responses in vitro, using either allogeneic or autologo ⁇ s T cells as responder cells(methods include lymphocyte proliferation, cytokme synthesis and release, cellular cytotoxicity, Elispot assays, etc).
  • cell surface and intracellular protein expression for example, cell surface molecules, T cell costimulatory ligand molecules
  • HLA antigen presenting molecules
  • known tumour antigens e.g. MAGE family, fusion proteins from gene translocations e.g. bcr/abl,
  • the invention further provides the use of a hybrid cell derived from an ex vivo tumour cell fused with a lymphoblastoid cell in the preparation of a medicament for the treatment of cancer.
  • a further aspect of the present invention provides a method of treating cancer, the method comprising administering a hybrid cell derived from an ex vivo tumour cell fused with a lymphoblastoid cell to a patient in need of such treatment.
  • the method may further comprise obtaining at least one tumour cell ex vivo, and fusing the tumour cell with at least one lymphoblastoid cell, to provide at least one hybrid cell.
  • the tumour cell may be obtained from the patient in need of such treatment, or the cell may be obtained from a different patient.
  • the present invention also provides a method of treating ex vivo tumour cells, the method comprising fusing the tumour cell with at least one lymphoblastoid cell, to provide at least one hybrid cell.
  • the method may also comprise the step of removing the tumour cell from a patient.
  • the hybrid cell may be returned to the same patient after fusion. Alternatively, the hybrid cell may be returned to a different patient.
  • a hybrid cell derived from an ex vivo tumour cell fused with a lymphoblastoid cell for use as a vaccine.
  • the invention also provides a hybrid cell derived from an ex vivo tumour cell fused with a lymphoblastoid cell. Cells of the present invention may be useful for purposes other than as vaccines and treatments.
  • tumour-specific immune responses in vitro, induction and expansion of tumour- specific effector cells (or other potential immune mediators) in vitro for adoptive transfer; tools for identifying novel tumour antigens; study of mechanisms involved in antigen-specific immune responses and / or oncogenesis.
  • a still further aspect of the present invention provides a method for generating hybrid cells, the method comprising obtaining at least one ex vivo tumour cell from a subject, and fusing the tumour cell with at least one lymphoblastoid cell.
  • Figure 1 shows a cell surface antigen expression phenotype for a particular hybrid cell type in accordance with an embodiment of the present invention
  • Figure 2 and 3 show stimulation of T cell proliferation in vitro by hybrid cells in accordance with an embodiment of the present invention.
  • the EBV B-LCL cell line HMy2 was used to generate APC / tumour cell hybrids by cell fusion with tumour cells in the presence of PEG / DMSO in accordance with established techniques.
  • Haematological tumour cells were obtained ex vivo from patients using conventional techniques.
  • the HMy2 cell line is resistant to ouabain, but sensitive to hypoxanthine, aminopterin and thymidine (HAT), allowing for chemical selection of hybrid cells in vitro.
  • Hybrid cell lines were analysed for the expression of cell surface markers by monoclonal antibody (mAb) staining of viable cells using immunofluorescence (IF) techniques, followed by flow cytometric analysis using a FACSCalibur flow cytometer (Becton Dickinson Ltd, Cowley, UK).
  • mAb monoclonal antibody
  • IF immunofluorescence
  • T cells Stimulation of proliferation of allogeneic (normal healthy donor) or autologous (patient from whom the tumour cells were derived) T cells was performed by co-culture (5 days, 37°, 5%CO2) of peripheral blood mononuclear cells or separated T cells with hybrid cells, parent EBV B-LCL or tumour cells, and was estimated by pulsing cultures with [3H]thymidine and harvested after incubation (overnight, 37°, 5% CO2) with a Tomtec cell harvester onto glass fibre filters. Incorporated radioactivity was measured (as counts per minute [c.p.m.]) in a Wallac 1450 Microbeta liquid scintillation counter. Results
  • a number of hybrids were made using EBV B-LCL and ex vivo haematological tumour cells.
  • the number of cell lines derived from various types of tumour was as follows.
  • B-CLL B cell chronic lymphocytic leukaemia
  • c-ALL common acute lymphoblastic leukaemia
  • Follicular lymphoma Mantle cell lymphoma
  • Multiple myeloma 5 Acute myeloid leukaemia 2 Analysis of the expression of cell surface markers was carried out as described.
  • Figure 1 shows a typical phenotype of one B-CLL hybrid (identified as hybrid MD049). Markers which were studied include CDS, CD19, CD40, CD1 la, CD50, CD54, CD58,
  • CD80, CD86, anti-HLA-ABC, and anti-HLA-DR The expression profile indicates that the hybrid cell (shaded plots) presents a largely identical profile to the parent EBV B-
  • LCL cell the lighter of the two line plots; the darker line plot refers to the parent tumour cells. Similar results were obtained for other hybrids. The stimulation of T cell proliferation in vitro by the hybrids was then studied.
  • FIGS 2 and 3 show, respectively, stimulation of allogeneic and autologous T cell proliferation in response to the indicated cells. It can be seen that the hybrid cells
  • the present inventor has performed a range of experiments to demonstrate the feasibility of the use of hybrid cells derived from ex vivo tumour cells as cellular vaccines.
  • Stable, self-propagating hybrid cell lines have been generated by ilision of EBV B-LCL with a range of haematological malignancies (including chronic lymphocytic leukaemia, ⁇ on-Hodgkin's lymphomas, acute lymphoblastic leukaemia, multiple myeloma, acute myeloid leukaemia).
  • haematological malignancies including chronic lymphocytic leukaemia, ⁇ on-Hodgkin's lymphomas, acute lymphoblastic leukaemia, multiple myeloma, acute myeloid leukaemia.
  • CD80 and CD86 where parent tumour cells lacked such expression.
  • tumour cells stimulate strong T cell proliferative responses in vitro (where unmodified tumour cells stimulated little or no response), where T cells derived from either normal healthy donor (allogeneic responses) or patient from whom the tumour cells were derived (autologous responses). Such responses are important for potential vaccine responses in vivo, to know that patients' immune cells are able to respond to the hybrid cells.
  • human tumour cell lines derived from solid tumours such as melanomas and cervical cancers.
  • hybrid cells We have further demonstrated expression of relevant tumour associated antigens by hybrid cells, showing a similar antigen expression to tumour cells from which the hybrids were derived; and we have demonstrated co-expression of HLA molecules derived from both parent cell lines (tumour cells and EBV B-LCL).
  • HLA molecules derived from both parent cell lines (tumour cells and EBV B-LCL).
  • the generation and production of hybrid cells from ex vivo tumour cells has a number of advantages for vaccine production over conventional techniques based on cell lines.

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Abstract

La présente invention concerne une technique de production de vaccin destiné au traitement ou à la prévention du cancer. Cette technique consiste à générer une cellule hybride par fusion d'une cellule tumoraleex vivo avec une cellule lymphoblastoïde. Des aspects de cette mention concernent aussi des cellules hybrides générées par cette technique et des utilisations de ces cellules dans la préparation de médicaments ou de vaccins destinés au traitement du cancer.
PCT/GB2005/050032 2004-03-24 2005-03-11 Vaccin a cellule hybride WO2005092371A1 (fr)

Applications Claiming Priority (2)

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GB0406598.3 2004-03-24
GBGB0406598.3A GB0406598D0 (en) 2004-03-24 2004-03-24 Vaccine

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008098042A1 (fr) * 2007-02-06 2008-08-14 Ghc Research Development Corporation Cellules hybrides
WO2015069770A1 (fr) * 2013-11-05 2015-05-14 Cognate Bioservices, Inc. Combinaisons d'inhibiteurs de point de contrôle et d'agents thérapeutiques pour traiter un cancer

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0163218A2 (fr) * 1984-05-31 1985-12-04 Sloan-Kettering Institute For Cancer Research Méthode de production d'hybridomes de cellules T-T humaines et production de facteur suppresseur par des hybridomes de cellules T-T humaines
EP1130088A1 (fr) * 2000-02-27 2001-09-05 Eberhard-Karls-Universität Tübingen Universitätsklinikum Vaccins composés de cellules hybrides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0163218A2 (fr) * 1984-05-31 1985-12-04 Sloan-Kettering Institute For Cancer Research Méthode de production d'hybridomes de cellules T-T humaines et production de facteur suppresseur par des hybridomes de cellules T-T humaines
EP1130088A1 (fr) * 2000-02-27 2001-09-05 Eberhard-Karls-Universität Tübingen Universitätsklinikum Vaccins composés de cellules hybrides

Non-Patent Citations (5)

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Title
DUNNION D J ET AL: "Human antigen-presenting cell/tumour cell hybrids stimulate strong allogeneic responses and present tumour-associated antigens to cytotoxic T cells in vitro.", IMMUNOLOGY. DEC 1999, vol. 98, no. 4, December 1999 (1999-12-01), pages 541 - 550, XP002327774, ISSN: 0019-2805 *
GONG J ET AL: "INDUCTION OF ANTITUMOR ACTIVITY BY IMMUNIZATION WITH FUSIONS OF DENDRITIC AND CARCINOMA CELLS", NATURE MEDICINE, NATURE PUBLISHING, CO, US, vol. 3, no. 5, May 1997 (1997-05-01), pages 558 - 561, XP002910553, ISSN: 1078-8956 *
KAEFFER B ET AL: "HISTOCOMPATIBLE MINIATURE PIG D-D HAPLOTYPE GENERATION OF HYBRIDOMAS SECRETING A OR M MONOCLONAL ANTIBODY", HYBRIDOMA, vol. 10, no. 6, 1991, pages 731 - 744, XP009047608, ISSN: 0272-457X *
KUGLER A ET AL: "AUTOLOGOUS AND ALLOGENIC HYBRID CELL VACCINE IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA", BJU. BRITISH JOURNAL OF UROLOGY, J & C EDICIONES MEDICAS, ESPLUGUES DE LLOBREGAT, ES, vol. 82, 1998, pages 487 - 493, XP001010074, ISSN: 1139-4757 *
KUGLER A ET AL: "REGRESSION OF HUMAN METASTATIC RENAL CELL CARCINOMA AFTER VACCINATION WITH TUMOR CELL-DENDRITIC CELL HYBRIDS", NATURE MEDICINE, NATURE AMERICA, NEW YORK, US, vol. 6, no. 3, March 2000 (2000-03-01), pages 332 - 336, XP001005439, ISSN: 1078-8956 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008098042A1 (fr) * 2007-02-06 2008-08-14 Ghc Research Development Corporation Cellules hybrides
WO2015069770A1 (fr) * 2013-11-05 2015-05-14 Cognate Bioservices, Inc. Combinaisons d'inhibiteurs de point de contrôle et d'agents thérapeutiques pour traiter un cancer

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