Too many “exhausted” T cells left in the wake of aggressive chemotherapy regimens for patients with advanced chronic lymphocytic leukemia (CLL) make it more challenging for chimeric antigen receptor (CAR) T-cell therapy to do its job. Now, a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania shows a potential method to overcome this type of resistance and reinvigorate these T cells with an experimental small-molecule inhibitor.
In a report published by Kong et al in the Journal of Clinical Investigation, the team wrote about how the drug, known as JQ1, improved CAR T-cell function by inhibiting bromodomain and extraterminal (BET) proteins. They showed that BET proteins can disrupt CAR expression and key acetylated histone functions in CLL T cells.
The findings demonstrate, for the first time, this mechanism of resistance and present a much-needed target for CLL when treating patients with cellular therapies like CAR. Only a small subset of patients with advanced CLL respond to CAR T-cell therapy, compared to 80% of patients with advanced acute lymphocytic leukemia.
“Why CAR T cells fail to fully attack cancer cells in so many patients with CLL is an important question that needs to be answered in order to expand the use of these immunotherapies in CLL and other cancers,” said senior study author Joseph A. Fraietta, PhD, Assistant Professor of Microbiology at Penn and member of the Center for Cellular Immunotherapies. “Treating these ‘war weary’ T cells during the CAR T-cell engineering process has the potential to boost responses, [as] 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.”
More Study Details
Using the small-molecule inhibitor alongside the T cells and CD19-targeted CAR T cells from multiple previously treated patients, the researchers demonstrated that the BET protein plays a role in downregulating CAR expression, and that, if blocked, can diminish CAR T-cell exhaustion and increase the production of CAR T cells from patients with CLL and poor lymphocytes.
Treatment with JQ1 also increased levels of various immunoregulatory cytokines and chemokines previously reported to be produced by CAR T cells in CLL during successful therapy. The array of native immune and CAR cells mirrored those found more typically in patients who do respond.
Given this observed reinvigoration of dysfunctional CAR T cells from patients with CLL by BET inhibition, the authors suggested that incorporating JQ1 into cellular engineering and expansion processes could lead to a generation of less defective and more potent final CAR T cells for patients. To what extent the above pathways contribute to the effects of JQ1 on CAR T cells is a focus of ongoing investigations for the research group.
“This work shows us that T cells can be taught new tricks,” said study coauthor Bruce Levine, PhD, the Barbara and Edward Netter Professor in Cancer Gene Therapy in Penn’s Perelman School of Medicine. “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.”
Disclosure: This work was supported by the Bob Levis Funding Group, along with the National Institute of Allergy and Infectious Diseases, National Cancer Institute, National Institute on Aging, the National Institute of General Medical Sciences, an Emerging Cancer Informatics Center of Excellence award from the Penn Institute for Biomedical Informatics and Abramson Cancer Center, Gabrielle’s Angel Foundation, an Alliance for Cancer Gene Therapy Investigator Award in Cell and Gene Therapy for Cancer, and Novartis. For full disclosures of the study authors, visit jci.org.
