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Chimeric antigen receptor T-cell therapies for lymphoma

Key Points

  • New treatments are needed for patients with chemotherapy-refractory or multiply-relapsed lymphoma

  • Chimeric antigen receptor (CAR) T cells targeting CD19 have demonstrated efficacy in multiple subtypes of B-cell lymphoma, with activity seen in patients with chemotherapy-refractory lymphoma; durable remissions are possible

  • Multicentre clinical trials have demonstrated that centralized CAR-T-cell processing is feasible, and response rates in early studies of centrally manufactured CAR-T-cell therapies are similar to those reported in single-centre studies

  • CARs targeting novel antigens, such as CD20, CD22, CD30 and κ light chains, are in development and will extend the applicability of CAR-T-cell therapy to patients with Hodgkin lymphoma, T-cell lymphoma, or CD19-negative B-cell lymphoma

  • Cytokine-release syndrome and neurological toxicity are severe adverse events commonly associated with CAR-T-cell therapies for lymphoma, and reducing the risk of such toxicities is a major avenue for improving CAR-T-cell therapies

  • CAR-T-cell therapy is likely to become safer and more effective, and will probably become a standard treatment option for patients with relapsed and primary-chemotherapy-refractory lymphoma in the near future

Abstract

New therapies are needed for patients with Hodgkin or non-Hodgkin lymphomas that are resistant to standard therapies. Indeed, unresponsiveness to standard chemotherapy and relapse after autologous stem-cell transplantation are indicators of an especially poor prognosis. Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment modality for these patients. Clinical trial data have demonstrated the potent activity of anti-CD19 CAR T cells against multiple subtypes of B-cell lymphoma, including diffuse large-B-cell lymphoma (DLBCL), follicular lymphoma, mantle-cell lymphoma, and marginal-zone lymphoma. Importantly, anti-CD19 CAR T cells have impressive activity against chemotherapy-refractory lymphoma, inducing durable complete remissions lasting >2 years in some patients with refractory DLBCL. CAR-T-cell therapies are, however, associated with potentially fatal toxicities, including cytokine-release syndrome and neurological toxicities. CAR T cells with novel target antigens, including CD20, CD22, and κ-light chain for B-cell lymphomas, and CD30 for Hodgkin and T-cell lymphomas, are currently being investigated in clinical trials. Centrally manufactured CAR T cells are also being tested in industry-sponsored multicentre clinical trials, and will probably soon become a standard therapy. Herein, we review the clinical efficacy and toxicity of CAR-T-cell therapies for lymphoma, and discuss their limitations and future directions with regard to toxicity management, CAR designs and CAR-T-cell phenotypes, conditioning regimens, and combination therapies.

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Figure 1: Chimeric antigen receptor (CAR) structures.
Figure 2: Different approaches to improving chimeric antigen receptor (CAR)-T-cell therapies.

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Correspondence to James N. Kochenderfer.

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J.N.K. receives research funding from cooperative research and development agreements between the National Cancer Institute (NCI) and Kite Pharma, and between the NCI and Bluebird Bio. J.N.K. also has multiple patent applications related to chimeric antigen receptors (CARs). J.N.B. declares no competing interests.

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Brudno, J., Kochenderfer, J. Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol 15, 31–46 (2018). https://doi.org/10.1038/nrclinonc.2017.128

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