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  • Review Article
  • Published:

Immunogenicity of CAR T cells in cancer therapy

Nature Reviews Clinical Oncology volume 18, pages 379–393 (2021)Cite this article

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Abstract

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.

Key points

  • 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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Fig. 1: Mechanisms of action of anti-CAR immune responses.
Fig. 2: Differences in anti-CAR immune responses following the targeting of B cell versus solid-tumour antigens.
Fig. 3: Engineering CAR T cells to reduce their inherent immunogenicity.
Fig. 4: Strategies to avoid immune elimination of allogeneic CAR T cells.
Fig. 5: Monitoring, mitigation and management of anti-CAR immunity in the clinic.

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Acknowledgements

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.

Review criteria

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.

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Author notes

  1. These authors contributed equally: Dimitrios L. Wagner, Enrico Fritsche.

Authors and Affiliations

  1. Berlin Center for Advanced Therapies (BeCAT) and Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin, Germany

    Dimitrios L. Wagner, Enrico Fritsche & Mohamed Abou-el-Enein

  2. Institute of Transfusion Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Dimitrios L. Wagner

  3. Section of Transplantation and Cellular Therapy, Children’s Hospital Los Angeles Cancer and Blood Disease Institute, USC Keck School of Medicine, Los Angeles, CA, USA

    Michael A. Pulsipher

  4. Texas Children’s Cancer and Hematology Centers, Texas Children’s Hospital, Houston, TX, USA

    Nabil Ahmed & Meenakshi Hegde

  5. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA

    Nabil Ahmed & Meenakshi Hegde

  6. Center for Cell Engineering and Immunology Program, Sloan Kettering Institute, New York, NY, USA

    Mohamad Hamieh

  7. Center for Cellular Immunotherapies, University of Pennsylvania Philadelphia, Philadelphia, PA, USA

    Marco Ruella

  8. Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Marco Ruella

  9. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    Barbara Savoldo

  10. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Nirali N. Shah

  11. Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA

    Cameron J. Turtle

  12. Department of Medicine, University of Washington, Seattle, WA, USA

    Cameron J. Turtle

  13. Cancer and Blood Disease Institute, Division of Hematology-Oncology, Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Alan S. Wayne

  14. Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Alan S. Wayne

  15. Division of Medical Oncology, Department of Medicine, and Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Mohamed Abou-el-Enein

  16. Joint USC/CHLA Cell Therapy Program, University of Southern California, and Children’s Hospital Los Angeles, Los Angeles, CA, USA

    Mohamed Abou-el-Enein

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Contributions

D.L.W., E.F. and M.A. researched data for the manuscript. All authors made a contribution to discussions of content. D.L.W., E.F., M.A.P., N.A., M.H.a., M.H.e., B.S., N.N.S., C.J.T., A.S.W. and M.A. wrote the manuscript. All authors edited and/or reviewed the manuscript prior to submission.

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Correspondence to Mohamed Abou-el-Enein.

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Competing interests

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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Nature Reviews Clinical Oncology thanks Marcela Maus and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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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