JQ1, a BET Inhibitor, Increases CAR T Efficacy and Durability

Article

Investigators sought to understand the mechanisms of transferred T cell proliferation and expression.

New research from the Perelman School of Medicine at the University of Pennsylvania has shown that JQ1, a small-molecule inhibitor currently used to treat a variety of cancers, can “reinvigorate” patient T cells and improve chimeric antigen receptor (CAR) T-cell therapy function.1

Investigators, including senior author Joseph A. Fraietta, PhD, assistant professor, microbiology, Penn, and member, Center for Cellular Immunotherapies, found that JQ1 inhibits the bromodomain and extra terminal (BET) proteins, which, in turn, disrupt CAR expression and T cell histone function in chronic lymphocytic leukemia (CLL).

“Why CAR T cells fail to fully attack cancer cells in so many CLL patients is an important question that needs to be answered in order to expand the use of these immunotherapies in CLL and other cancers,” Fraietta said in a statement.1 “Treating these ‘war weary’ T cells during the CAR T cell engineering process has the potential to boost responses, we’ve shown here. It’s setting the stage for a very promising set of next steps that rationalize further studies, including clinical trials, to prove this approach is safe and feasible.”

Fraietta and colleagues used longitudinal immune profiling in patients with CLL to observe phenotypic and pharmacodynamic changes in their CD-20 targeted CAR T cells. They also investigated CAR expression maintenance. The investigators saw that CAR T cell failure was accompanied by defects or dysfunction in the T cells acquired after infusion and, in a small subset of patients, leukemia relapse.2

READ MORE: New Partnership Will Assess Clinical Potential of CAR T-Cell Therapy, Oncolytic Virus Combination in Solid Tumors

Among 46 patients who underwent infusion, overall response rate was 51%, with only 28% of heavily pretreated patients obtaining sustained complete responses. Looking more closely, they saw that patients with less expansion of their transferred T cells had less response than those with proliferative and persistent transferred T cells. Between these groups, the investigators found that patients that responded the least had an early failure of the CAR T cells compared with responders whose CAR T cells quickly reduced disease burden.

The investigators demonstrated the role of the BET family of chromatin adapters in downregulating CAR expression. They also demonstrated that blocking BET expression yielded a reduction in inhibitory receptors, increased proliferative capacity, and enhanced metabolic fitness of CAR T cells, as well as other enriched transcriptomic signs of their reinvigoration. 

Fraietta and colleagues postulated that modulating BET epigenetic readers may improve cell-based immunotherapies based on the mechanism they discovered that BET inhibition decreased levels of TET2 methylcytosine dioxygenase and forced expression of the TET2 catalytic domain. This eliminated the potency-enhancing effects of CAR T-cell targeting of BET protein.

“This work shows us that T cells can be taught new tricks,” added co-author Bruce Levine, PhD, the Barbara and Edward Netter Professor in Cancer Gene Therapy, Perelman School of Medicine.1 “That is to say that the methods of manufacturing can be adapted to improve CAR T cell function, so that what would have been exhausted or dysfunctional cells can now be reinvigorated, and potentially lead to better clinical responses in more patients than before.”

REFERENCES
1. Existing drug may help improve responses to cellular therapies in advanced leukemias. News release. Penn Medicine. August 16, 2021. https://www.pennmedicine.org/news/news-releases/2021/august/existing-drug-may-help-improve-responses-to-cellular-therapies-in-advanced-leukemias
2. Kong W, Dimitri A, Wang W, et al. BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia. J Clin Invest. 2021;131(16):1-16. doi:10.1172/JCI145459
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