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A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains

Nature Reviews Clinical Oncology volume 18, pages 715–727 (2021)Cite this article

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Abstract

Chimeric antigen receptors (CARs) are engineered proteins designed to target T cells to cancer cells. To effectively activate the T cells in which they are expressed, CARs must contain a costimulatory domain. The CAR T cell products approved for the treatment of B cell lymphomas and/or acute lymphoblastic leukaemia or multiple myeloma incorporate either a CD28-derived or a 4-1BB-derived costimulatory domain. Almost all other clinically tested CARs also use costimulatory domains from CD28 or 4-1BB. In preclinical experiments, cytokine release is usually greater with CARs containing CD28 versus 4-1BB costimulatory domains; however, constructs with either domain confer similar anticancer activity in mouse models. T cell products expressing CARs with either CD28 or 4-1BB costimulatory domains have been highly efficacious in patients with relapsed haematological malignancies, with anti-CD19 products having similar activity regardless of the source of the costimulatory domain. In large-cohort clinical trials, the rates of neurological toxicities have been higher with CD28-costimulated CARs, although this finding is probably the result of a combination of factors rather than due to CD28 signalling alone. Future preclinical and clinical research should aim to compare different costimulatory domains while controlling for confounding variables. Herein, we provide an overview of T cell costimulation by CD28 and 4-1BB and, using the available preclinical and clinical data, compare the efficacy and toxicity profiles associated with CARs containing either costimulatory domain.

Key points

  • Commercial anti-CD19 chimeric antigen receptor (CAR) T cell products have been approved for the treatment of patients with B cell lymphomas or B cell acute lymphoblastic leukaemia, and an anti-B cell maturation antigen CAR T cell product has been approved for the treatment of patients with multiple myeloma.

  • The inclusion of a costimulatory domain in the CAR construct is required for optimal CAR T cell survival, cytokine production and tumour eradication in vivo.

  • The costimulatory domains most often utilized in CARs are derived from CD28 and/or 4-1BB. In endogenous T cells, CD28 and 4-1BB differ in expression pattern and intracellular signalling.

  • Data from mouse models have not demonstrated consistently superior anticancer activity with CARs containing either a CD28 or a 4-1BB costimulatory domain.

  • In clinical trials, the efficacy of anti-CD19 CAR T cells expressing CD28-containing CARs and those expressing 4-1BB-containing CARs has been similar.

  • Cytokine release syndrome rates vary across trials, with no clear associations depending on whether a CD28-containing or a 4-1BB-containing CAR was used.

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Fig. 1: T cell costimulation.
Fig. 2: Incorporating costimulation into CAR design.

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Acknowledgements

The work of the authors is supported by National Cancer Institute intramural funding. The figures included in this manuscript were originally drafted using BioRender.com and subsequently redrawn by Nature Reviews Clinical Oncology prior to publication.

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  1. Hematology Oncology Fellowship Program, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA

    Kathryn M. Cappell

  2. Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA

    James N. Kochenderfer

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The authors contributed equally to all aspects of the article.

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Correspondence to James N. Kochenderfer.

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Competing interests

J.N.K. receives research funding and royalties on CAR inventions from Kite, a Gilead Company, and also receives research funding from Bristol-Myers Squibb. K.M.C. declares no competing interests.

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

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Cappell, K.M., Kochenderfer, J.N. A comparison of chimeric antigen receptors containing CD28 versus 4-1BB costimulatory domains. Nat Rev Clin Oncol 18, 715–727 (2021). https://doi.org/10.1038/s41571-021-00530-z

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