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Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion

Abstract

Chimeric antigen receptor (CAR) T cells have emerged as a potent therapeutic approach for patients with certain haematological cancers, with multiple CAR T cell products currently approved by the FDA for those with relapsed and/or refractory B cell malignancies. However, in order to derive the desired level of effectiveness, patients need to successfully receive the CAR T cell infusion in a timely fashion. This process entails apheresis of the patient’s T cells, followed by CAR T cell manufacture. While awaiting infusion at an authorized treatment centre, patients may receive interim disease-directed therapy. Most patients will also receive a course of pre-CAR T cell lymphodepletion, which has emerged as an important factor in enabling durable responses. The time between apheresis and CAR T cell infusion is often not a simple journey, with each milestone being a critical step that can have important downstream consequences for the ability to receive the infusion and the strength of clinical responses. In this Review, we provide a summary of the many considerations for preparing patients with B cell non-Hodgkin lymphoma or acute lymphoblastic leukaemia for CAR T cell therapy, and outline current limitations and areas for future research.

Key points

  • Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of certain forms of acute lymphoblastic leukaemia and B cell non-Hodgkin lymphoma; a deeper understanding of the considerations for patient preparation and management prior to infusion will probably further improve outcomes.

  • Bridging therapies and lymphodepleting regimens are both becoming important components of treatment with CAR T cell therapy; however, the available approaches often vary between patients, products and treating centres.

  • Bridging therapy can be comprised of a host of therapeutic options, including standard chemotherapy or, alternatively, immunotherapy and/or radiotherapy.

  • Patient-specific considerations, including the contexts of eligibility and timing of CAR T cell infusion, are imperative to determining the optimal treatment approach.

  • Here, we review the emerging data on patient selection, bridging therapies and lymphodepletion regimens administered before CAR T cell infusion, all of which are critical to improving clinical outcomes.

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Fig. 1: Antibody-based targeted therapies used in various bridging therapies and lymphodepletion regimens.
Fig. 2: Chemotherapies and small molecules used in various bridging therapies and lymphodepletion regimens.

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Acknowledgements

This work was supported in part by the Intramural Research Program, Center of Cancer Research, US National Cancer Institute, National Institutes of Health (ZIA BC 011823, N.N.S.). The authors would like to thank Professor Richard Grose (Barts Cancer Institute, Queen Mary University of London, UK) for his critical review of the figures. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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L.A., S.K.S., N.S. and M.A. researched data for this manuscript, all authors made a substantial contribution to discussions of content, L.A., S.K.S., N.S. and M.A. wrote the manuscript, and all authors reviewed and/or edited the manuscript prior to submission.

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Correspondence to Mohamed Abou-el-Enein.

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S.L.M. has acted as a consultant and/or adviser of and has received research funding from Novartis and Wugen. L.J.N. has received honoraria from ADC Therapeutics, Bayer, BMS/Celgene, Epizyme, Genentech, Gilead/Kite, Janssen, Morphosys, Novartis, Pfizer, TG Therapeutics; and has received research funding from BMS/Celgene, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, IGM Biosciences, Janssen, Novartis, Pfizer, TG Therapeutics. C.A.R. has acted as an adviser of Novartis and has received research funding from Athenex and Tessa Therapeutics. R.J.B. has licensed intellectual property to and collects royalties from BMS, Caribou and Sanofi; has received research funding from BMS; has acted as a consultant of Atara Biotherapeutics, BMS and Gracell Biotechnologies. C.S.S. has acted as a consultant of Celgene/BMS, Gamida Cell, Genmab, GSK, Juno Therapeutics, Karyopharm Therapeutics, Kite/a Gilead Company, Novartis, Precision Biosciences, Sanofi-Genzyme, and Spectrum Pharmaceuticals and has received research funding from Celgene/BMS, Bristol-Myers Squibb, Juno Therapeutics, Precision Biosciences and Sanofi-Genzyme. L. A., S.K.S., N.N.S. and M.A. declare no competing interests.

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Amini, L., Silbert, S.K., Maude, S.L. et al. Preparing for CAR T cell therapy: patient selection, bridging therapies and lymphodepletion. Nat Rev Clin Oncol 19, 342–355 (2022). https://doi.org/10.1038/s41571-022-00607-3

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