PerspectiveIMMUNOTHERAPY

Reversal of exhaustion in engineered T cells

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Science  02 Apr 2021:
Vol. 372, Issue 6537, pp. 34-35
DOI: 10.1126/science.abh0583

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Summary

As T cell therapies for cancer and viral disease enter mainstream medicine (13), identifying impediments to their therapeutic activity is crucial. Persistent stimulation of virus- or tumor-specific T cells through their antigen-specific T cell receptor (TCR) can lead to progressive loss of effector function, a phenomenon called functional exhaustion (4, 5). A similar outcome may occur in therapeutic T cells engineered with synthetic chimeric antigen receptors (CARs), which bypass the native TCR and directly activate T cells upon binding to surface tumor antigen. In both cases, exhaustion is associated with continuous stimulation through the antigen receptor, impairing expansion and target cell lysis. On page 49 of this issue, Weber et al. (6) show that continuous CAR stimulation induces profound functional, transcriptional, and epigenetic changes in CAR–T cells that are reversed by intermittent blockade of CAR signaling. One of their approaches to reversal uses an approved drug (dasatinib), enabling its rapid clinical evaluation.

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