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  • Review Article
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Optimizing the manufacturing and antitumour response of CAR T therapy

Nature Reviews Bioengineering volume 1, pages 271–285 (2023)Cite this article

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Abstract

Adoptive transfer of naturally occurring or genetically engineered T cells is an effective treatment for certain haematological malignancies, such as non-Hodgkin lymphoma and acute lymphoblastic leukaemia, but still faces challenges in treating solid tumours. The phenotype of the final T cell product substantially affects in vivo antitumour efficacy, and various strategies have been developed to manipulate T cell phenotype during chimeric antigen receptor (CAR)-expressing T cell manufacturing to improve in vivo responses after T cell infusion. In this Review, we provide an overview of specific T cell attributes that influence the performance of adoptive T cell transfers, including memory T cell population, CD4:CD8 composition and CD4 subsets. Moreover, we discuss how different T cell subsets interact with and are affected by the immunosuppressive tumour microenvironment, including the role of preconditioning in CAR T therapies. We then review strategies to control T cell phenotype and antitumour performance after infusion through manipulation of the three signals for T cell activation and downstream signalling pathways during manufacturing. We finish by discussing developments in rapid manufacturing of CAR T cell products.

Key points

  • Phenotypes of chimeric antigen receptor T (CAR T) cell products, including CD4:CD8 ratio, memory composition and specific CD4+ T cell subsets, affect clinical efficacy after adoptive transfer.

  • The tumour microenvironment hinders the efficacy of CAR T cells, but preconditioning can benefit CAR T therapy by remodelling the tumour microenvironment.

  • CAR T cell products can be finely tuned and improved through manipulation of the three signals for T cell activation and their downstream signalling pathways.

  • CAR T cell products can be modified to directly communicate with the host immune system, thereby prolonging their in vivo persistence and preventing exhaustion.

  • Rapid manufacturing and in vivo expansion can reduce the time and resources needed for CAR T cell manufacturing, thereby making CAR T therapy more accessible.

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Fig. 1: T cell memory phenotypes affect antitumour capability.
Fig. 2: CD4+ T cell subset composition and the tumour microenvironment affect the outcome of ACT treatment.
Fig. 3: Controlling CAR T cell phenotype by modulating the three signals for T cell activation.
Fig. 4: Additional strategies to modulate the CAR T phenotype.

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Authors and Affiliations

  1. John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA

    Yutong Liu & David J. Mooney

  2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA

    Yutong Liu & David J. Mooney

  3. Division of Hematology, Brigham and Women’s Hospital, Boston, MA, USA

    Adam S. Sperling

  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Adam S. Sperling & Eric L. Smith

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Y.L. and A.S.S. researched data and wrote the manuscript. Y.L., A.S.S., E.L.S. and D.J.M. discussed the content, reviewed and edited the manuscript.

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Competing interests

A.S.S. has consulted for Adaptive Technologies. E.L.S. has had research funded by Bristol Myers Squibb and Sanofi, is on the scientific advisory boards of Bristol Myers Squibb, Sanofi, and Chimeric Therapeutics and the data safety monitoring board of Eureka Therapeutics, has consulted for Chroma Medicine, ImmuneBridge, Secura Bio, Clade Therapeutics, Sana Biotech and Allogene, and holds licensed patents for BCMA and GPRC5D targeted CAR T cells licensed to Bristol Myers Squibb and for GPRC5D targeted antibody therapies licensed through Sanofi. D.J.M. has had research sponsored by Novartis, has consulted for Medicenna, Johnson & Johnson and IVIVA Medical, and has equity in Lyell and Attivare. Y.L. declares no competing interest.

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Liu, Y., Sperling, A.S., Smith, E.L. et al. Optimizing the manufacturing and antitumour response of CAR T therapy. Nat Rev Bioeng 1, 271–285 (2023). https://doi.org/10.1038/s44222-023-00031-x

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