Investigating BET Inhibitors to Improve CAR T Therapy: Joseph A. Fraietta, PhD

“JQ1 is the prototype BET inhibitor, and it was great for proof of concept. Other compounds target BRD4 more specifically. In my own lab, we're testing these more BRD4-specific inhibitors to see if we get the same effect – it looks like we are, but the data are preliminary at the moment. It's always good when you can specifically hit your target without having off-target effects and JQ1 hits not only BRD4, but also other proteins as well. Specificity is key, and we just need to fine tune that a bit before translation.”

Researchers from the University of Pennsylvania’s Perelman School of Medicine found that JQ1, a small-molecule inhibitor currently used to treat a variety of cancers, “reinvigorates” patient T cells and thus can address the issue of exhausted T cells in chimeric antigen receptor (CAR) T-cell therapy durability and function.

Joseph A. Fraietta, PhD, assistant professor, microbiology, and director, Solid Tumor Immunotherapy Lab, Center for Advanced Cellular Therapies, University of Pennsylvania, and colleagues found that JQ1 inhibits the bromodomain and extra terminal (BET) proteins, which would otherwise disrupt T cell histone function and CAR expression in chronic lymphocytic leukemia (CLL).

GeneTherapyLive spoke with Fraietta to learn more about other BET inhibitors that could be more appropriate for patients. He discussed future research he would like to conduct with BET inhibitors and CAR T-cell therapy and how these inhibitors could fit into the treatment landscape.

REFERENCE

Existing drug may help improve responses to cellular therapies in advanced leukemias. News release. University of Pennsylvania. August 16, 2021. https://www.pennmedicine.org/news/news-releases/2021/august/existing-drug-may-help-improve-responses-to-cellular-therapies-in-advanced-leukemias