Abstract
Chimeric antigen receptor (CAR) T cells have been approved for use in patients with B cell malignancies or relapsed and/or refractory multiple myeloma, yet efficacy against most solid tumours remains elusive. The limited imaging and biopsy data from clinical trials in this setting continues to hinder understanding, necessitating a reliance on imperfect preclinical models. In this Perspective, I re-evaluate current data and suggest potential pathways towards greater success, drawing lessons from the few successful trials testing CAR T cells in patients with solid tumours and the clinical experience with tumour-infiltrating lymphocytes. The most promising approaches include the use of pluripotent stem cells, co-targeting multiple mechanisms of immune evasion, employing multiple co-stimulatory domains, and CAR ligand-targeting vaccines. An alternative strategy focused on administering multiple doses of short-lived CAR T cells in an attempt to pre-empt exhaustion and maintain a functional effector pool should also be considered.
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Acknowledgements
The input of A. Bott (Capstan Therapeutics) and J. Fraietta, B. Levine, E. Noguera-Ortega, M. Sellmyer, D. Powell, E. Puré and Z. Xiao (all from the University of Pennsylvania), along with the administrative assistance of M. McNichol are highly appreciated.
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S.A. has acted as a scientific adviser to Bio4t2 LLC and Verismo Therapeutics, has received research support from Capstan, Novartis and Tmunity and is a founder of Capstan Therapeutics.
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Albelda, S.M. CAR T cell therapy for patients with solid tumours: key lessons to learn and unlearn. Nat Rev Clin Oncol 21, 47–66 (2024). https://doi.org/10.1038/s41571-023-00832-4
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DOI: https://doi.org/10.1038/s41571-023-00832-4
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