Dr. Marco Ruella and his collaborators at the University of Pennsylvania are working to develop combination strategies that will improve outcomes for cancer patients treated with the adoptive cell transfer approach called chimeric antigen receptor (CAR) T-cell therapy. For standard CAR T-cell treatment, T cells are genetically engineered with a receptor specific to the cancer of interest. However, CAR T-cell therapy outcomes in blood cancers vary widely – from ~90% complete remission in some patient groups to ~30%-50% in others. In patients with solid tumors, the results tend to be very poor. Dr. Ruella and his team believe combination therapy could be the answer and are using novel high throughput technologies to discover small molecules that enhance CAR T-cell potency. They are testing thousands of CAR T-cell/small molecule combinations to find those that enhance the tumor-killing properties of the CAR T cells. The team is also studying whether small molecules that inhibit tumor growth by promoting cell death, known as SMAC mimetics, improve the effectiveness of CAR T-cell therapy. Their preliminary results suggest the two drug classes have a synergistic effect in enhancing tumor killing. This work will not only improve CAR T-cell therapy but will also lead to a pipeline of small molecule drugs that could be relevant for other T-cell immunotherapies.
Singh N, Lee YG, Shestova O, Ravikumar P, Hayer KE, Hong SJ, Lu XM, Pajarillo R, Agarwal S, Kuramitsu S, Orlando EJ, Mueller KT, Good CR, Berger SL, Shalem O, Weitzman MD, Frey NV, Maude SL, Grupp SA, June CH, Gill S, Ruella M. Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction. Cancer Discov. 2020.