Transient inhibition of CAR signaling was capable of preventing and reversing CAR T-cell exhaustion.
Major Finding: Transient inhibition of CAR signaling was capable of preventing and reversing CAR T-cell exhaustion.
Concept: Rest remodeled the exhaustion-associated epigenetic landscape and rescued CAR T-cell function.
Impact: This study reveals a strategy to combat exhaustion and improve efficacy of CAR T-cell therapy.
Chimeric antigen receptor (CAR) T cells are engineered from a patient's own T cells to recognize and attack tumor antigen–expressing cancer cells, but clinical responses are often limited by T-cell exhaustion. To investigate whether transient inhibition of CAR signaling could enhance CAR T-cell function, Weber and colleagues developed a drug-regulable system to control CAR expression, showing that transient reductions in CAR levels during CAR T-cell expansion enhanced cytotoxicity, reducing xenograft tumor growth and prolonging survival after adoptive cell transfer. In an in vitro model of CAR T-cell exhaustion in which exhaustion phenotypes were acquired following a given duration of cell culture, CAR protein was destabilized prior to the onset of exhaustion, decreasing coexpression of exhaustion-related inhibitory receptors and redirecting cell fate from an exhausted phenotype to a memory-like phenotype. To investigate whether transient rest could not only prevent but also reverse exhaustion, CAR protein was destabilized after the onset of exhaustion, showing that rest from CAR signaling reversed phenotypic and transcriptomic hallmarks of exhaustion in vitro and rescued antitumor function in vivo. Mechanistically, transient rest, either before or after the onset of exhaustion, reprogrammed the exhaustion-associated epigenome, mediated in part through the activity of chromatin modifier EZH2. Induction of rest by suppression of CAR T-cell activation via the tyrosine kinase inhibitor dasatinib during in vitro expansion was also capable of improving antitumor function, with restoration of CAR T-cell function being positively correlated with duration of rest. In liquid- and solid-tumor xenograft models, intermittent rest mediated by in vivo dasatinib administration or CAR protein degradation reduced tumor growth and enhanced survival. This work not only supports that exhaustion-associated epigenetic reprogramming is reversible, but also suggests that transient inhibition of CAR signaling may be beneficial in the context of clinical manufacturing of CAR T-cell products as well as mitigating T-cell exhaustion during the course of CAR T-cell therapy.
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