Patient-derived T cells genetically reprogrammed to express CD19-specific chimeric antigen receptors (CARs) have shown remarkable clinical responses and are commercially available for the treatment of patients with certain advanced-stage B cell malignancies. Nonetheless, several trials have revealed pre-existing and/or treatment-induced immune responses to the mouse-derived single-chain variable fragments included in these constructs. These responses might have contributed to both treatment failure and the limited success of redosing strategies observed in some patients. Data from early phase clinical trials suggest that CAR T cells are also associated with immunogenicity-related events in patients with solid tumours. Generally, the clinical implications of anti-CAR immune responses are poorly understood and highly variable between different CAR constructs and malignancies. These observations highlight an urgent need to uncover the mechanisms of immunogenicity in patients receiving CAR T cells and develop validated assays to enable clinical detection. In this Review, we describe the current clinical evidence of anti-CAR immune responses and discuss how new CAR T cell technologies might impact the risk of immunogenicity. We then suggest ways to reduce the risks of anti-CAR immune responses to CAR T cell products that are advancing towards the clinic. Finally, we summarize measures that investigators could consider in order to systematically monitor and better comprehend the possible effects of immunogenicity during trials involving CAR T cells as well as in routine clinical practice.
Pre-existing and/or treatment-induced immunity to chimeric antigen receptor (CAR) constructs containing mouse-derived single-chain variable fragments are associated with treatment failure in certain patients and might limit the success of redosing strategies.
The possible effects of immunogenicity on CAR T cell persistence and function are currently poorly understood.
Novel technologies designed to enhance CAR T cell performance and/or the application of allogeneic CAR T cells might further amplify the likelihood of anti-CAR immune responses, thus necessitating strategies to overcome such risks.
Various monitoring, mitigation and management approaches can be used to reduce the risk of anti-CAR immunity, although validated assays enabling adequate assessments of anti-CAR immune responses remain an unmet need.
We advocate for the inclusion of CAR-associated immunogenicity analysis in both preclinical and clinical investigations of CAR T cell therapy.
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The work of N.A. and M.H. is supported by the US NIH PHS grant U54-CA23256 and by Stand Up to Cancer–St Baldrick’s Paediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). The work of A.S.W. is supported by the US National Cancer Institute [P30CA014089]. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services nor does its mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. The authors thank Catherine Gillespie (Baylor College of Medicine, USA) for her assistance in editing the manuscript and thank Naomi Taylor and Christopher Chien (Pediatric Oncology Branch, National Cancer Institute, NIH, USA) for their critical review of the figures.
We conducted a literature screen and identified 120 clinical trial publications describing the use of chimeric antigen receptor (CAR) T cells, out of which 34 reported on the investigation of immunogenicity using laboratory assays (Box 1). A complete list of these trials, including information on the assays used to characterize immunogenicity, CAR design, trial outcomes and preconditioning regimens, is available in Supplementary Table 1. Data cut-off July 15, 2020.
M.A.P. has acted as an advisor for Mesoblast and Novartis, has received research funding from Adaptive and Miltenyi, and has received honoraria for educational activities from Miltenyi and Novartis. N.A. has acted as a consultant for Adaptimmune and continues to consult for Equillium (pro bono) and The Children’s Cancer Hospital Egypt 57357 on medical education and research development, has received one-time royalties from Celgene and Cell Medica, and is a named inventor on patents and patent applications in the field of chimeric antigen receptor (CAR) T cell therapy owned by Baylor College of Medicine. M. Hamieh is listed on patents relating to CAR technologies and has received royalties from Atara Biotherapeutics, Fate Therapeutics and Takeda Pharmaceuticals. M. Hegde is a named inventor on patents and patent applications in the field of CAR T cell therapy owned by Baylor College of Medicine. M.R. has acted as a consultant of AbClon, Bristol-Myers Squibb (BMS), Mesoblast, NanoString, and Novartis, has received research support from Adaptive and Miltenyi, and is listed on patents relating to CAR technologies and receives royalties from Novartis and Tmunity. B.S. has acted as a consultant of Tessa Therapeutics, has received research funding from Bellicum Pharmaceuticals, Bluebird Bio, Cell Medica and Tessa Therapeutics, and is listed on patents in the field of CAR and T cell receptor (TCR) therapy. C.J.T. has served on the scientific advisory boards of ArsenalBio, Caribou Biosciences, Century Therapeutics, Eureka Therapeutics, Myeloid Therapeutics, Precision Biosciences and T-CURX, has acted as an ad hoc consultant of Allogene, Amgen, AstraZeneca, Nektar Therapeutics and PACT Pharma, has stock/options in ArsenalBio, Caribou Biosciences, Eureka Therapeutics, Myeloid Therapeutics and Precision Biosciences, has received research funding from AstraZeneca, Juno Therapeutics/BMS, Minerva, Nektar Therapeutics and TCR2 Therapeutics, and is listed on a patent licensed to Juno Therapeutics. A.S.W. has received research support from Kite Pharma and Institut de Recherches Internationales Servier. E.F., D.L.W., N.N.S. and M.A. declare no competing interests.
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Wagner, D.L., Fritsche, E., Pulsipher, M.A. et al. Immunogenicity of CAR T cells in cancer therapy. Nat Rev Clin Oncol 18, 379–393 (2021). https://doi.org/10.1038/s41571-021-00476-2
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