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  • Review Article
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Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

Nature Reviews Clinical Oncology volume 20, pages 49–62 (2023)Cite this article

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Abstract

Therapies with genetically modified T cells that express chimeric antigen receptors (CARs) specific for CD19 or B cell maturation antigen (BCMA) are approved to treat certain B cell malignancies. However, translating these successes into treatments for patients with solid tumours presents various challenges, including the risk of clinically serious on-target, off-tumour toxicity (OTOT) owing to CAR T cell-mediated cytotoxicity against non-malignant tissues expressing the target antigen. Indeed, severe OTOT has been observed in various CAR T cell clinical trials involving patients with solid tumours, highlighting the importance of establishing strategies to predict, mitigate and control the onset of this effect. In this Review, we summarize current clinical evidence of OTOT with CAR T cells in the treatment of solid tumours and discuss the utility of preclinical mouse models in predicting clinical OTOT. We then describe novel strategies being developed to improve the specificity of CAR T cells in solid tumours, particularly the role of affinity tuning of target binders, logic circuits and synthetic biology. Furthermore, we highlight control strategies that can be used to mitigate clinical OTOT following cell infusion such as regulating or eliminating CAR T cell activity, exogenous control of CAR expression, and local administration of CAR T cells.

Key points

  • Chimeric antigen receptor (CAR) T cell therapies have led to on-target, off-tumour toxicity (OTOT) in clinical trials involving patients with solid tumours.

  • Preclinical mouse models might provide inaccurate predictions of OTOT in patients, reflecting the need for better models to perform preclinical safety assessments.

  • Logic-gating circuits and synthetic biology approaches to CAR T cell engineering have demonstrated specificity in mice, although many of these approaches remain untested in clinical studies.

  • Methods of controlling CAR T cell activity and responding to unexpected OTOT have the potential to improve safety after infusion.

  • We advocate for robust preclinical analyses of the risks of OTOT and the implementation of control strategies capable of regulating CAR T cell activity in patients.

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Fig. 1: CAR architecture.
Fig. 2: CAR T cell cytolytic mechanisms and paracrine effects.
Fig. 3: Publicly available protein expression densities of selected solid tumour TAAs on non-malignant tissues.
Fig. 4: Principles of Boolean logic-gating to circumvent OTOT.
Fig. 5: Examples of logic-gating strategies tested in CAR T cells.
Fig. 6: Control switches in CAR T cells.
Fig. 7: Regional restriction of CAR T cell activity.

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Acknowledgements

The authors thank K. T. Roybal (University of California, San Francisco, USA) for his helpful comments on an earlier draft of the manuscript. They thank A. Cadinanos-Garai (University of Southern California, USA) for her critical review of the manuscript and figures. The work of G.K. is supported by R01NS121249 from NINDS and the Assisi Foundation of Memphis. The work of M.A. is supported, in part, by award P30CA014089 from the US NIH National Cancer Institute (NCI).

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Author notes

  1. These authors contributed equally: Dimitrios L. Wagner and Mohamed Abou-el-Enein.

Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Christian L. Flugel & Mohamed Abou-el-Enein

  2. BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health (BIH) at Charité–Universitätsmedizin Berlin, Berlin, Germany

    Christian L. Flugel & Dimitrios L. Wagner

  3. Department of Paediatrics, Stanford University School of Medicine, Stanford, CA, USA

    Robbie G. Majzner

  4. Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA

    Robbie G. Majzner

  5. Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children’s Research Hospital, Memphis, TN, USA

    Giedre Krenciute

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

    Gianpietro Dotti

  7. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Gianpietro Dotti

  8. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Stanley R. Riddell

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

    Stanley R. Riddell

  10. Berlin Center for Advanced Therapies (BeCAT), Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Dimitrios L. Wagner

  11. Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Mohamed Abou-el-Enein

  12. 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

C.L.F, D.L.W. and M.A. researched data for the manuscript, all authors made a substantial contribution to discussions of content. C.L.F., D.L.W. and M.A. wrote the manuscript, and all authors reviewed and/or edited the manuscript prior to submission.

Corresponding author

Correspondence to Mohamed Abou-el-Enein.

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Competing interests

R.G.M. has acted as an adviser and/or consultant of Aptorum Group, Arovella Therapeutics, Immunai, Innervate Radiopharmaceuticals, Link Cell Therapies, Lyell Immunopharma, NKarta, Syncopation Life Sciences, and Zai lab and is a co-founder of and holds equity in Syncopation Life Sciences and Link Cell Therapies. G.K. has patent applications in the field of immunotherapy. G.D. has acted as a scientific adviser and/or consultant of Bellicum Pharmaceutical and Catamaran and Tessa Therapeutics and holds patents in the field of CAR T cells. S.R.R. has acted as a scientific adviser of Adaptive Biotechnologies and Juno Therapeutics, is a co-founder of and has intellectual property licensed to Lyell Immunopharma and Juno Therapeutics, and holds shares in and has received research funding from Lyell Immunopharma. C.L.F., D.L.W. and M.A. declare no competing interests.

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Flugel, C.L., Majzner, R.G., Krenciute, G. et al. Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours. Nat Rev Clin Oncol 20, 49–62 (2023). https://doi.org/10.1038/s41571-022-00704-3

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