Researchers identify potential approach to overcoming CLL CAR T-cell resistance

The findings, if confirmed in subsequent research, could prove to have important implications, as only a small subset of patients with CLL respond to CAR T-cell therapy, which is the majority (80% of patients with acute lymphocytic leukemia). ) is opposite. Advanced diseases that respond.

“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,” said Joseph a. Freetta, PhD, said. Assistant Professor of Microbiology at the Perelman School of Medicine, member of the Center for Cellular Immunotherapy and senior author of the study, said in a statement. “Treating these ‘battle tired’ T cells during the CAR T-cell engineering process has the potential to boost responses we have shown here. This is setting the stage for a very promising set of next steps.” Which rationalizes further studies, including clinical trials, to prove this approach is safe and feasible.”

research, published in Journal of Clinical Investigation, is the first to describe the BET family of chromatin adapters as a driver in downregulating CAR expression, say the researchers, who also found that blocking the protein with the experimental small molecule inhibitor JQ1 prevented CAR T-β-cell expression. Cell exhaustion was improved and CAR production increased. T cells. This was demonstrated by evidence of inhibitory receptor depletion, increased metabolic fitness, enhanced fertility and T-cell resorption.

Notably, JQ1 increased the levels of several immunoregulatory cytokines and chemokines, which have been described in successful cases of CLL with CAR T-cell therapy. According to the researchers, this finding was observed in cells stimulated with the CD19+ K562 target with and without PD-1 ligation.

The study findings are the result of longitudinal immune profiling that identified phenotypic and pharmacodynamic changes in CAR T cells in CLL.

“This work shows us that T cells can be taught new tricks,” Bruce Levine, PhD, the Barbara and Edward Netter Professor in Cancer Gene Therapy at Perelman and co-author of the study, said in the statement. “This is to say that manufacturing methods can be adapted to improve CAR T-cell function, so that cells that have been depleted or dormant can now regenerate and potentially be better in more patients than ever before.” to produce clinical responses.”

According to the researchers, the findings shown in their study could be applied to a variety of adoptive immunotherapy platforms and help to rationalize more potent treatments or in vivo combinations of epigenetic drugs and engineered T cells.

Reference

Kong W, Dimitri A, Wang W, et al. Beta bromodomain protein inhibition reverses chimeric antigen receptor extinction and rejuvenates depleted T cells in chronic lymphocytic leukemia. J Clin Invest. 2021; 131(16:1-16). doi: 10.1172/jci145459

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