Comparative analysis of assays to measure CAR T cell-mediated cytotoxicity
Open accessAbstract
The antitumor efficacy of genetically engineered 'living drugs', including chimeric antigen receptor and T-cell receptor T cells, is influenced by their activation, proliferation, inhibition, and exhaustion. A sensitive and reproducible cytotoxicity assay that collectively reflects these functions is an essential requirement for translation of these cellular therapeutic agents. Here, we compare various in vitro cytotoxicity assays (including chromium release, bioluminescence, impedance, and flow cytometry) with respect to their experimental setup, appropriate uses, advantages, and disadvantages, and measures to overcome their limitations. We also highlight the US Food and Drug Administration (FDA) directives for a potency assay for release of clinical cell therapy products. In addition, we discuss advanced assays of repeated antigen exposure and simultaneous testing of combinations of immune effector cells, immunomodulatory antibodies, and targets with variable antigen expression. This review article should help to equip investigators with the necessary knowledge to select appropriate cytotoxicity assays to test the efficacy of immunotherapeutic agents alone or in combination.
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A U.S. company that seeks to manufacture CAR T-cells in the U.S. and E.U. must comply with both sets of regulations and work with strict oversight from both the FDA and EMA to meet respective manufacturing standards.
“A U.S. company that seeks to manufacture CAR T-cells in the U.S. and E.U. must comply with both sets of regulations and work with strict oversight from both the FDA and the European Medicines Agency (EMA) to meet respective manufacturing standards (133,135,136).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [133]
The Introduction’s “Potency assays for clinical cell therapy products” section describes requirements for potency testing and discusses FDA-approved CAR T-cell products. It does not address EMA oversight or say that a U.S. company manufacturing in both the U.S. and E.U. must comply with both sets of manufacturing regulations. (LLM, conf=0.83)
Experimental — accuracy not yet measuredA similar clinical trial phase structure exists in the European Union, although some GMP regulations are stricter in Europe.
“A similar clinical trial phase structure exists in the European Union, although some GMP regulations are stricter in Europe (132,133).”
From Scalable Manufacturing of CAR T Cells for Cancer Immunotherapy (2021) · cites this paper as [133]
The Introduction section on potency assays describes requirements by clinical-study phase but does not compare EU and US trial structures. Searches for European clinical-trial phases and stricter European GMP regulations found no passage addressing either comparison in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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A 3D in vitro assay to study combined immune cell infiltration and cytotoxicityPreprint
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GMP Manufacturing of Allogenic iPSC-NK Cells for Immunotherapy
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CliCAR: A non-genetic CAR engineering strategy to empower NK cells for targeted cancer immunotherapy
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Advances in Gene Therapy with Oncolytic Viruses and CAR-T Cells and Therapy-Related Groups
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A New Approach to In Vivo Transformation of Killer T Cells
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Cellular Immunogenicity Assessments in CAR-T Cell Therapies: Current Insights and Future Directions
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Multi-parametric profiling of IL-7-augmented GD2.CART products in a phase 1 clinical trial
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Potency Assay Development: A Keystone for Clinical Use
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Immunotherapy in cancer: Where we are and what the future brings?
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Challenges and future perspectives for high-throughput chimeric antigen receptor T cell discovery
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Current Role of CAR-T Therapy in Haematological Care
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A 3D multi-compartment assembloid to study combined immune cell infiltration and cytotoxicity
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Celldetective, an AI-enhanced image analysis tool for unraveling dynamic cell interactionsPreprint
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Preclinical studies using CAR-T cells.
Kerbauy, L. N., de Godoy, J. A. P., Paiva, R. M. A., Kondo, A. T., Okamoto, O. K., & Bonamino, M. (2022) · JOURNAL OF BONE MARROW TRANSPLANTATION AND CELLULAR THERAPY · doi:10.46765/2675-374x.2022v3n1p154
- Authors
- Kiesgen, S., Messinger, J. C., Chintala, N. K., Tano, Z., & Adusumilli, P. S.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Adusumilli, Prasad S.
- Venue
- Nature Protocols
- Published
- 2021-02-15
- Volume
- 16
- Issue
- 3
- Pages
- 1331-1342
- ISSN
- 1750-2799 (ISSN-L)
- 1754-2189
- PMC
- PMC8064272
- OpenAlex
- W3132904428
- Cited by
- 138
- References
- 100
- Citations by year
- 2026: 24 · 2025: 37 · 2024: 32 · 2023: 22 · 2022: 18 · 2021: 5
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Protocols (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA236615, R01CA235667, P30CA008748, T32CA009501)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- chimeric antigen receptor T cells, T cell cytotoxicity, chromium release assay, bioluminescence assay, flow cytometry, potency assay, T cell exhaustion, T cell proliferation, combination immunotherapy, immunomodulatory antibodies, T cell receptor T cells
- MeSH terms
- Receptors, Chimeric Antigen, Animals, Cytotoxicity Tests, Immunologic, Flow Cytometry, Humans, Receptors, Antigen, T-Cell, T-Lymphocytes, Immunotherapy, Adoptive, Xenograft Model Antitumor Assays
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