CN113109572A - Method for detecting somatic immunogenicity of autologous CART cells - Google Patents
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- 230000005847 immunogenicity Effects 0.000 title claims abstract description 14
- 230000000392 somatic effect Effects 0.000 title claims description 4
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- 238000011282 treatment Methods 0.000 claims abstract description 13
- 239000013642 negative control Substances 0.000 claims abstract description 9
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6854—Immunoglobulins
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56966—Animal cells
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
- G01N33/582—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with fluorescent label
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2469/00—Immunoassays for the detection of microorganisms
- G01N2469/20—Detection of antibodies in sample from host which are directed against antigens from microorganisms
Abstract
The invention provides a method for detecting the humoral immunogenicity of autologous CART cells. The invention uses the autologous T cells of the testee without CAR modification as negative control target cells, uses the autologous CART cells of the testee after CAR modification as target cells for detection, and compares the difference of the reactivity of the tested serum sample of the testee and the reactivity of the two target cells by a flow cytometry technology, thereby judging whether the antibodies against CAR exist in the tested serum sample of the testee. The invention not only can help a clinician to screen a CAR modification method which is not easy to cause a patient to generate an anti-CAR antibody before CART treatment is carried out on the patient, but also can be used as a etiology detection means for dynamically monitoring the failure of CART treatment caused by the induction of the anti-CAR antibody in CART cell treatment, so that the CART cell can exert the maximum treatment effect.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to a method for detecting autologous CART cell humoral immunogenicity.
Background
A Chimeric Antigen Receptor T Cell (CART) is a Receptor (CAR) which can recognize specific targets of tumor cells and is expressed on the surface of the T cell of a patient in a Chimeric way by a genetic engineering method, so that autologous T cells modified by the CAR can recognize and kill the tumor cells in the body of the patient and can be used for treating tumors.
Clinical experiments show that autologous T cells of a patient are embedded with a Chimeric Antigen Receptor (CAR) which can specifically bind to a B cell surface marker CD19 on the surface of the T cells after genetic engineering, and the engineered autologous T cells, namely CD19-CART cells, have very remarkable curative effect in treating malignant tumors of certain B cell types expressing CD 19. Such treatment methods were approved by the U.S. food and drug administration FDA in 2017 and are commercially available.
Researchers have discovered from previous clinical practices that some patients have a pre-existing immune response to the chimeric antigen receptor CAR in vivo prior to receiving CART cell therapy; and after other patients receive CART treatment, because the chimeric antigen receptor CAR of genetically engineered recombination non-self source is chimeric on the autologous T cells of the patients in the preparation process of the CART cells, the CART cells stimulate the patients to generate immune response to the CAR after entering the bodies of the patients. Immune responses to the chimeric antigen receptor CAR, whether pre-existing before the patient receives CART cell therapy or induced post-therapy, are the primary reason for direct failure of CART cell therapy, or failure to repeat therapy again. Based on the above reasons, whether to screen the most suitable CART cells and make them exert their optimal therapeutic effects in the treated patients or to analyze the exact pathological reasons of the ineffective CART treatment, we need to establish a complete set of complete detection methods to more comprehensively analyze and identify the immunogenicity of the CART cells to the treated patients.
At present, methods for detecting the humoral immunogenicity of Chimeric Antigen Receptors (CARs) on the surface of autologous CART cells are mainly divided into two categories, one is to directly use purified CARs as protein antigens for detection and detect corresponding anti-CAR IgG antibodies in the serum of patients by enzyme-linked immunosorbent assay (ELISA); another class is the detection of corresponding anti-CAR IgG antibodies in patient serum by flow cytometry using CAR-expressing T lymphoma cells (Jurkat T cells) or Chinese Hamster Ovary cells (Chinese Hamster Ovary (CHO) cells) as target cells (Nat Rev Clin Oncol.2021Feb 25.doi:10.1038/s 41571-021-00476-2).
Disclosure of Invention
In view of the technical problems, the invention provides a method for detecting the humoral immunogenicity of autologous CART cells, which can be used for detecting whether a chimeric antigen receptor CAR expressed on the surface of a T cell of a patient can cause the patient to generate a corresponding humoral immune response through a gene recombination technology, namely, an anti-CAR antibody is generated.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for detecting humoral immunogenicity of autologous CART cells, comprising: and (3) using the autologous T cells of the testee which are not modified by the CAR as negative control target cells, using the autologous CART cells of the testee which are modified by the CAR as target cells for detection, and comparing the difference of the reactivity of the tested serum sample of the testee and the reactivity of the two target cells by a flow cytometry technology so as to judge whether the anti-CAR antibody exists in the tested serum sample of the testee.
Preferably, the flow cytometry detection result shows negative reaction to the autologous T cells of the testee without the CAR modification whether the anti-CAR antibodies exist in the detected serum sample or not, and the negative reaction is used as a negative control; if the serum of the tested person does not contain the anti-CAR antibody, the tested serum sample and CART cell react in the same way as negative control and show negative reaction; if anti-CAR antibodies were present in the subject serum, the antibodies would bind to CAR on the surface of CART cells and then bind positively with fluorescein-labeled anti-human immunoglobulin antibodies.
More preferably, the fluorescein-labeled anti-human immunoglobulin antibody may be selected according to the type of the target detection antibody, and may be a fully reactive fluorescein-labeled antibody that recognizes all types of immunoglobulins, or a fluorescein-labeled antibody specific to IgM, IgG, IgE, IgA, or a subtype thereof.
Preferably, the anti-CAR antibody can comprise an IgM, an IgG, an IgE, an IgA, or a mixture of two or more antibodies.
Preferably, different treatment methods are adopted for the detected serum sample of the testee according to different requirements on the type of the detected target antibody:
i. if it is only necessary to detect whether the subject produces antibodies against CAR, and it is not necessary to distinguish the type of antibody, the serum to be tested may be left untreated;
if the type or subtype of the anti-CAR antibody is to be confirmed so that the detection of the anti-CAR antibody is not interfered by the detection of other types of antibodies, the serum sample to be tested is classified, purified and separated in advance, and purified to obtain IgM, IgG, IgE, IgA or its subtype (e.g., IgM1, 2, IgG1, 2, 3, 4; IgA1, 2, etc.), and then the purified antibody fractions are subjected to the detection of the corresponding CAR antibodies.
The invention has the following beneficial effects:
the invention judges whether the detected serum sample of the testee contains the anti-CAR antibody by comparing different reactivities of autologous T cells of the testee to the serum of the patient before and after the autologous T cells are modified by the chimeric antigen receptor CAR. The detection method can help a clinician screen a CAR modification method which is not easy to cause a patient to generate an anti-CAR antibody before CART treatment is performed on the patient, and avoid CART treatment failure caused by the anti-CAR antibody; and the kit can be used as a etiological detection means for dynamically monitoring the possible failure of CART treatment due to the induction of anti-CAR antibodies in the CART cell treatment, and the detection result can guide the clinical adoption of corresponding immunological adjuvant treatment means for controlling or eliminating the anti-CAR antibodies, so that the CART cells can exert the maximum treatment effect.
Drawings
FIG. 1 is a flow chart of a method of the invention for detecting the humoral immunogenicity of autologous CART cells.
FIG. 2 flow cytometry results of the present invention: A. reaction results of purified isolated autologous T cells in patient serum and peripheral blood; B. results of the reaction of patient sera and CD 19-specific CAR engineered autologous CART cells.
Detailed Description
The present invention is described in further detail by referring to the following examples. The examples are for illustrative purposes only and should not be construed as limited to the methods described in this example, but rather should be construed to include any and all variations of the methods of practice provided herein and which become apparent therefrom.
In the following examples, patient sera were used, all with informed consent, meeting relevant use criteria. Meanwhile, the following experimental reagents and methods are all laboratory-routine reagents and methods, unless otherwise specified.
Example assay for anti-CAR antibodies
With reference to fig. 1, the method comprises the following steps:
1. taking 3-5 ml of anticoagulated peripheral blood of a patient, and separating and purifying peripheral blood T cells by a magnetic bead sorting method.
2. Not less than 50,000 purified peripheral blood T cells were counted as negative control target cells, washed 3 times with RPMI medium, and finally the T cells were suspended in 50 μ l of RPMI cell medium, and the centrifuge tube was placed on ice.
3. The same number of CD 19-specific autologous CART cells were counted as target cells for detection of anti-CAR antibodies, washed 3 times with RPMI culture solution, and finally the CART cells were suspended in 50 μ l of RPMI cell culture solution, and the centrifuge tubes were placed on ice.
4. And respectively adding the same amount of serum of the patient, which is not less than 10 microliters, into the centrifuge tubes of the T cells and the CART cells.
5. The serum and the cells in the tube were mixed well, the tube was placed on ice and incubated for 30 minutes.
6. Not less than 1 ml of RPMI culture solution is added into a centrifuge tube to clean cells, and the supernatant is removed after centrifugation.
7. Washing was repeated three times, and finally the above T cells and CART cells were suspended in about 50. mu.l of RPMI culture solution, respectively.
8. 10 microliters of mouse anti-human IgG-PE (concentration 100. mu.g/ml) was added to each of the cells in the two tubes, and the antibody and the cells in the tubes were mixed well, and the tubes were placed on ice and incubated for 30 minutes.
9. Not less than 1 ml of RPMI culture solution is added into two centrifuge tubes to clean cells, and supernatant is removed after centrifugation.
10. Washing was repeated three times, and finally the above T cells and CART cells were suspended in 200. mu.l of RPMI medium, respectively.
11. The flow cytometry results are shown in fig. 2.
FIG. 2A shows the reaction results of purified and isolated autologous T cells in patient serum and peripheral blood, and this was set as a negative reaction reference value for the detection reaction.
By comparing with the negative reaction reference value set in fig. 2A, the fluorescence intensity of CART cells after the binding reaction between the serum and CART cells detected this time and the fluorescence intensity of autologous T cells serving as negative control target cells are close to each other, and the interval distribution of the fluorescence reaction values of the two groups of cells almost completely overlap, so that the detection result of the anti-CAR antibody at this time is determined to be negative.
Claims (5)
1. A method for detecting humoral immunogenicity of autologous CART cells, comprising: and (3) using the autologous T cells of the testee which are not modified by the CAR as negative control target cells, using the autologous CART cells of the testee which are modified by the CAR as target cells for detection, and comparing the difference of the reactivity of the tested serum sample of the testee and the reactivity of the two target cells by a flow cytometry technology so as to judge whether the anti-CAR antibody exists in the tested serum sample of the testee.
2. The method for detecting the somatic immunogenicity of autologous CART cells according to claim 1, wherein the flow cytometry detection result shows a negative reaction to the autologous T cells of the testee without CAR modification, regardless of the presence or absence of anti-CAR antibodies in the serum sample to be detected, and the negative reaction is used as a negative control; if the serum of the tested person does not contain the anti-CAR antibody, the tested serum sample and CART cell react in the same way as negative control and show negative reaction; if anti-CAR antibodies were present in the subject serum, the antibodies would bind to CAR on the surface of CART cells and then bind positively with fluorescein-labeled anti-human immunoglobulin antibodies.
3. The method for detecting somatic immunogenicity of autologous CART cells according to claim 2, wherein the fluorescein-labeled anti-human immunoglobulin antibody is selected according to the type of target detection antibody, and comprises a fully reactive fluorescein-labeled antibody that recognizes all types of immunoglobulins, or a fluorescein-labeled antibody specific to IgM, IgG, IgE, IgA or subtypes thereof.
4. The method for detecting humoral immunogenicity of autologous CART cells according to claim 1, wherein said anti-CAR antibodies comprise IgM, IgG, IgE, IgA, or a mixture of two or more antibodies.
5. The method for detecting the humoral immunogenicity of autologous CART cells according to claim 1, wherein different treatments are applied to the serum sample of the subject according to different requirements for the type of target antibody to be detected:
i. if only the test subject needs to generate the anti-CAR antibody, and the type of the antibody does not need to be distinguished, the test serum is not processed;
if the type or subtype of the anti-CAR antibody needs to be confirmed, and the detection of the anti-CAR antibody is not interfered by the detection of other types of antibodies, the serum sample to be detected needs to be classified, purified and separated in advance, and IgM, IgG, IgE and IgA or subtypes thereof are respectively purified, and then the purified antibody components are respectively subjected to the detection of corresponding CAR antibodies.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023025364A1 (en) * | 2021-08-24 | 2023-03-02 | Fida Biosystems Aps | A method of determining an immunogenic response characteristic of a chemical substance |
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