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Mechanisms of resistance to chimeric antigen receptor-T cells in haematological malignancies

Nature Reviews Drug Discovery volume 22, pages 976–995 (2023)Cite this article

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Abstract

Chimeric antigen receptor (CAR)-T cells have recently emerged as a powerful therapeutic approach for the treatment of patients with chemotherapy-refractory or relapsed blood cancers, including acute lymphoblastic leukaemia, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma and multiple myeloma. Nevertheless, resistance to CAR-T cell therapies occurs in most patients. In this Review, we summarize the resistance mechanisms to CAR-T cell immunotherapy by analysing CAR-T cell dysfunction, intrinsic tumour resistance and the immunosuppressive tumour microenvironment. We discuss current research strategies to overcome multiple resistance mechanisms, including optimization of the CAR design, improvement of in vivo T cell function and persistence, modulation of the immunosuppressive tumour microenvironment and synergistic combination strategies.

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Fig. 1: Overview of CAR-T cell resistance mechanisms.
Fig. 2: Mechanisms of CAR-T cell dysfunction.
Fig. 3: Tumour-intrinsic mechanisms of resistance to CAR-T cells.
Fig. 4: Tumour microenvironment barriers to CAR-T cell therapy.

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Acknowledgements

The authors thank the National Cancer Institute (NCI) for their funding support (MVM R01 CA238268, R01 CA252940, R01 CA249062 and P01 CA233412). F.K. receives funding by the German Research Foundation (466535590). M.R. and P.P. are supported by the NCI R37-CA-262362-02 (to M.R.), the Leukemia and Lymphoma Society (to M.R.), the Hairy Cell Leukemia Foundation (to M.R.), the Gilead Research Scholar Award in Hematology (to M.R.), the Emerson Collective (to M.R.), the Laffey-McHugh Foundation (to M.R.), the Parker Institute for Cancer Immunotherapy (to M.R.), the Berman and Maguire Funds for Lymphoma Research at Penn (to M.R.), the Laffey-McHugh Fund (to M.R.), T32 Hematology Research Training Program (to P.P.) and the Lymphoma Research Foundation (to M.R.).

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Author notes

  1. These authors contributed equally: Marco Ruella, Felix Korell, Patrizia Porazzi.

Authors and Affiliations

  1. Division of Hematology and Oncology and Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA

    Marco Ruella & Patrizia Porazzi

  2. Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Boston, MA, USA

    Felix Korell & Marcela V. Maus

  3. Harvard Medical School, Boston, MA, USA

    Felix Korell & Marcela V. Maus

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  1. Marco Ruella
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All authors researched data for the article, contributed substantially to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Marcela V. Maus.

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Competing interests

M.R. holds patents related to chimeric antigen receptor-T cells that are managed by the University of Pennsylvania, and some of them are licensed to Novartis, Tmunity and viTToria Biotherapeutics. M.R. has served as a consultant for BMS, GSK, Scailyte, Bayer, GLG and AbClon. M.R. receives research funding from viTToria Biotherapeutics, ONI, Beckman Coulter and AbClon. M.R. is the scientific founder of viTToria Biotherapeutics. M.V.M. is an inventor on patents related to chimeric antigen receptor-T cell therapies held by the University of Pennsylvania (some licensed to Novartis) and Massachusetts General Hospital (some licensed to Promab and Satellite Bio). M.V.M. holds equity in 2Seventy Bio, TCR2, Century Therapeutics, Oncternal and Neximmune, and has served as a consultant for multiple companies involved in cell therapies. M.V.M. serves on the Board of Directors of 2Seventy Bio. F.K. and P.P. declare no competing interests.

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Glossary

Apheresis

A method by which the blood of a person is passed through a device that separates one particular constituent and returns the remainder to circulation.

Bystander killing

The activation of surrounding T cells in the absence of chimeric antigen receptor-T cell-induced antigen recognition. This bystander killing is important for the eradication of antigen-negative target cells as well as for overall therapy response.

CD45RO−

CD45 (also known as lymphocyte common antigen) is a receptor-bound protein tyrosine phosphatase that is expressed on leukocytes and has different isoforms. CD45RA T cells define a ‘naive’ trait, whereas CD45RO T cells are classified as ‘memory’ T cells.

Eastern Cooperative Oncology Group

A status scale widely used to assess the functional status of a patient.

Immune effector cell-associated neurotoxicity syndrome

Sometimes synonymously referred to as neurotoxicity, a clinical syndrome that can occur in the first days to weeks after chimeric antigen receptor-T cell administration. The symptoms, which in most cases are self-regulating and completely regress, range from mild confusion to life-threatening and sometimes fatal neurological complications, with application of steroids as the current standard of care.

Immunological synapse

The space between chimeric antigen receptor-T cells and the antigen-presenting tumour cell, in which the immune response is regulated and triggered by molecular interactions.

International Prognostic Index

The most frequently used prognostic factor system for patients with aggressive non-Hodgkin lymphoma.

Lymphohistiocytosis

A rare but sometimes fatal condition, caused mainly by infection, in which certain types of white blood cells (histiocytes and lymphocytes) can accumulate in various organs. These cells and other blood cells can be severely damaged or destroyed.

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Ruella, M., Korell, F., Porazzi, P. et al. Mechanisms of resistance to chimeric antigen receptor-T cells in haematological malignancies. Nat Rev Drug Discov 22, 976–995 (2023). https://doi.org/10.1038/s41573-023-00807-1

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