Abstract
The remarkable clinical activity of chimeric antigen receptor (CAR) therapies in B cell and plasma cell malignancies has validated the use of this therapeutic class for liquid cancers, but resistance and limited access remain as barriers to broader application. Here we review the immunobiology and design principles of current prototype CARs and present emerging platforms that are anticipated to drive future clinical advances. The field is witnessing a rapid expansion of next-generation CAR immune cell technologies designed to enhance efficacy, safety and access. Substantial progress has been made in augmenting immune cell fitness, activating endogenous immunity, arming cells to resist suppression via the tumour microenvironment and developing approaches to modulate antigen density thresholds. Increasingly sophisticated multispecific, logic-gated and regulatable CARs display the potential to overcome resistance and increase safety. Early signs of progress with stealth, virus-free and in vivo gene delivery platforms provide potential paths for reduced costs and increased access of cell therapies in the future. The continuing clinical success of CAR T cells in liquid cancers is driving the development of increasingly sophisticated immune cell therapies that are poised to translate to treatments for solid cancers and non-malignant diseases in the coming years.
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Change history
20 June 2023
A Correction to this paper has been published: https://doi.org/10.1038/s41586-023-06088-3
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Acknowledgements
C.L.M. and L.L are members of the Parker Institute for Cancer Immunotherapy, which supports the Stanford University Cancer Immunotherapy Program. This work was supported by the St Baldrick’s Foundation Empowering Pediatric Immunotherapies for Childhood Cancer (EPICC) Team and NCI 5P30CA124435 (C.L.M.). L.L. was supported by a Siebel Scholars Fellowship, Stanford Graduate Fellowship, National Science Foundation Graduate Research Fellowship (DGE-1656518), and Discovery Innovation Award philanthropically supported through the Biomedical Innovation Initiative.
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L.L. and C.L.M. are inventors on several patents related to CAR T cell therapies. C.L.M. is a cofounder of Lyell Immunopharma, CARGO Therapeutics and Link Cell Therapies, which are developing CAR-based therapies, and consults for Lyell, Syncopation, Link, Apricity, Nektar, Immatics, Ensoma, Mammoth, Glaxo Smith Kline and Bristol Myers Squibb. L.L. is a cofounder of, consults for, and holds equity in CARGO Therapeutics. L.L. is a consultant for and holds equity in Lyell Immunopharma.
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Labanieh, L., Mackall, C.L. CAR immune cells: design principles, resistance and the next generation. Nature 614, 635–648 (2023). https://doi.org/10.1038/s41586-023-05707-3
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DOI: https://doi.org/10.1038/s41586-023-05707-3
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