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Engineering-enhanced CAR T cells for improved cancer therapy

Nature Cancer volume 2, pages 780–793 (2021)Cite this article

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An Author Correction to this article was published on 24 September 2021

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Abstract

Chimeric antigen receptor (CAR) T cell therapies have evolved from a research tool to a concept-shifting therapy with impressive responses in B cell malignancies. This Review summarizes the current state of the CAR T cell field, focusing on CD19- and B cell maturation antigen-directed CAR T cells—the most developed of the CAR T cell therapies. We discuss the many challenges to CAR T cell therapeutic success and innovations in CAR design and T cell engineering aimed at extending this therapeutic platform beyond hematologic malignancies.

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Fig. 1: B cell malignancies at the different stages of B cell development.
Fig. 2: Operational pipeline for integrating correlative studies in translational science laboratories.
Fig. 3: Current strategies to overcome the hurdles of poor response to autologous CAR T cell therapy.
Fig. 4: CAR design limitations that affect clinical responses following CAR T cell treatment, and potential solutions.

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Acknowledgements

This work was supported by funding from the National Institutes of Health (R01CA241762 and R01GM138908 to J.J.M.), Stand up to Cancer Convergence 2.0 Grant (to J.J.M.), Parker Institute for Cancer Immunotherapy (J.J.M. and M.A.C.), National Natural Science Foundation of China (81970189), National Visiting Scholar Program of the China Scholarship Council and Guang-Ci Visiting Scholar Program of Ruijin Hospital affiliated to Shanghai Jiao Tong University (to J.X.).

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Authors and Affiliations

  1. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Michael C. Milone, Jie Xu, McKensie A. Collins, Daniel J. Powell Jr & J. Joseph Melenhorst

  2. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Michael C. Milone, Jie Xu, McKensie A. Collins, Daniel J. Powell Jr & J. Joseph Melenhorst

  3. Department of Hematology, Shanghai Institute of Hematology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Jie Xu & Sai-Juan Chen

  4. Immunotherapy Research Center for Hematologic Diseases of Hubei Province, Tianjin, People’s Republic of China

    Jianfeng Zhou

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J.J.M. developed the concept of the paper. All authors contributed to the first draft of the manuscript and approved the final version.

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Correspondence to J. Joseph Melenhorst.

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Competing interests

J.J.M., D.J.P. Jr and M.C.M. are inventors on several patents issued and pending in the field of CAR T cell therapy for cancer, which are assigned to the University of Pennsylvania. Under the University of Pennsylvania’s policies, J.J.M., D.J.P. Jr and M.C.M. either currently, or may in the future, receive royalties from the licensing of these patent rights. M.C.M. is an inventor on issued and pending patents related to CAR technology, and receives royalties from the licensing of this IP. He is also a founder and equity holder in Cabaletta Bio. J.X., S.-J.C. and M.A.C. have no conflicts of interest. J.Z. receives research funding from and is chairman of the Medical and Scientific Advisory Board of IASO Biotherapeutics. D.J.P. Jr is or has provided consultation for Iovance Biotherapeutics, Bellicum Pharmaceuticals, Neon Therapeutics, and Tmunity Therapeutics, and holds patents in the areas of tumor-infiltrating lymphocytes and gene-engineered T cells. J.J.M. receives research funding from IASO Biotherapeutics, consult for Simcere of America, Shanghai Unicar Therapy, Johnson & Johnson, Poseida, and IASO Biotherapeutics, and is on the Medical and Scientific Advisory Board of IASO Biotherapeutics and Poseida Therapeutics. J.J.M. further holds patents related to CAR T cell manufacturing and biomarkers.

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Milone, M.C., Xu, J., Chen, SJ. et al. Engineering-enhanced CAR T cells for improved cancer therapy. Nat Cancer 2, 780–793 (2021). https://doi.org/10.1038/s43018-021-00241-5

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