Researchers Identify Potential Approach to Overcoming CLL CAR T-Cell Resistance

The findings, if confirmed in subsequent research, could prove to have significant implications, as only a small subset of patients with chronic lymphocytic leukemia (CLL) respond to chimeric antigen receptor (CAR) T-cell therapy.

Modulating BET epigenetic readers may enhance the efficacy of chimeric antigen receptor (CAR) T-cell treatments in chronic lymphocytic leukemia (CLL), suggests new research. Doing so could promote a possible approach to addressing T-cell exhaustion from chemotherapy.

T-cell exhaustion makes it less likely for CAR T-cell therapy to work effectively in these patients.

The findings, if confirmed in subsequent research, could prove to have significant implications, because only a small subset of patients with CLL respond to CAR T-cell therapy, in stark contrast to the majority (80%) of patient with acute lymphocytic leukemia with advanced disease who 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. Fraietta, PhD, an assistant professor of microbiology at the Perelman School of Medicine, member of the Center for Cellular Immunotherapies, and senior author of the study, in a statement. “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.”

The research, published in the 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 improved CAR T-cell exhaustion and enhanced the production of CAR T cells. This was demonstrated by inhibitory receptor reduction, enhanced metabolic fitness, increased proliferative capacity, and evidence of T-cell reinvigoration.

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

The findings of the study 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,” explained Bruce Levine, PhD, the Barbara and Edward Netter Professor in Cancer Gene Therapy at Perelman and co-author on the study, in the statement. “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.”

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

Reference

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