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Insight into next-generation CAR therapeutics: designing CAR T cells to improve clinical outcomes
Emiliano Roselli, … , Rawan Faramand, Marco L. Davila
Emiliano Roselli, … , Rawan Faramand, Marco L. Davila
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(2):e142030. https://doi.org/10.1172/JCI142030.
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Insight into next-generation CAR therapeutics: designing CAR T cells to improve clinical outcomes

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Abstract

Chimeric antigen receptor (CAR) T cell therapy has shown considerable promise for hematologic malignancies, leading to the US Food and Drug Administration approval of two CAR T cell–based therapies for the treatment of B cell acute lymphoblastic leukemia and large B cell lymphoma. Despite success in hematologic malignancies, the treatment landscape of CAR T cell therapy for solid tumors has been limited. There are unique challenges in the development of novel CAR T cell therapies to improve both safety and efficacy. Improved understanding of the immunosuppressive tumor microenvironment and resistance mechanisms has led to encouraging approaches to mitigating these obstacles. This Review will characterize challenges with current CAR T designs for hematologic malignancies and solid tumors and emphasize preclinical and clinical strategies to overcome them with novel CAR T cell therapies.

Authors

Emiliano Roselli, Rawan Faramand, Marco L. Davila

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Figure 2

Overcoming toxicities through CAR-engineering strategies.

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Overcoming toxicities through CAR-engineering strategies.
CAR T cells sh...
CAR T cells show different levels of activation and cytokine production depending on (A) costimulatory domain, (B and C) length of the transmembrane domain, and (D) nature and composition of the hinge/transmembrane domain (E). CAR T cells have been engineered to secrete soluble IL-1 receptor antagonists or induce a targeted deletion on the gene encoding for GM-CSF associated with toxicities (F). Administration of a protease inhibitor controls CAR surface expression, acting as an “on/off switch” based on a complex composed of a self-cleaving protease and a degron moiety. TM, transmembrane; AICD, activation-induced cell death.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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