Jan Joseph Melenhorst, PhD

Modulation of TET2 Activity to Promote Chimeric Antigen Receptor T-Cell Expansion and Therapeutic Efficacy

In the past decade, we have learned that gene-modified immune cells can be very effective at fighting cancer. These therapies use man-made “chimeric antigen receptors” (CAR) which specifically target a protein expressed by cancer cells. However, challenges remain, some of which have been identified by the current applicants. Our work also has revealed mechanisms in which we can augment the anti-cancer potency of CAR T cells. Some of these mechanisms converge on a protein known as TET2. In other words, while the current commercially available CAR T cell therapies may fail in many leukemia patients, we have discovered ways to safely boost the anti-tumor function of T cells using small molecule-based mechanisms. This work is rooted in mechanistic studies we published and follow-up work between the laboratories of both applicants. Dr. Melenhorst’s lab has demonstrated that the inhibition of TET2 dramatically boosts CAR T cell function in a leukemia patient and in our in vitro studies. Dr. Jha, a leading expert in the biochemistry and medicinal chemistry of TET2, discovered that an FDA-approved drug, Eltrombopag, inhibits TET function. The ultimate goal of our work is to evaluate the clinical impact of TET2-modulated immune gene therapies in cancer.