Diwakar Davar, MD

Biography

I am currently an Associate Professor in the Division of Hematology-Oncology in the Department of Medicineat University of Pittsburgh. My initial work evaluated outcomes of melanoma patients treated with HD IL-2; andour data suggested that HD IL-2 administration in a non-ICU setting did not compromise outcomes. Isubsequently evaluated whether the addition of immunomodulatory doses of pegylated IFN (peg-IFN)improved upon PD-1 blockade in advanced PD-1 naïve melanoma; and we showed that the combinationresulted in 61% ORR with 46% 2-year PFS and that response was associated with IFN-γ gene expression andCD8 T cell infiltrate.Based on emerging data implicating intestinal dysbiosis in mediating PD-1 non-response in melanoma, Ideveloped a protocol evaluating responder-derived fecal microbiota transplant (FMT) in PD-1 refractorymelanoma. In this first-in-human effort, we demonstrated that microbiome modulation reversed resistance toimmunotherapy in a subset of melanoma patients by altering levels of immunosuppressive myeloid cells andwere published in Science. Concurrently, by evaluating a large unique dataset, and re-analyzing existingdatasets, we identified unique gut microbial signatures of response and immune-related adverse events to anti-PD-1 therapy. In this work published in Nat Med, we develop the concept of “gut microbial communities(microbiotypes)” and their variable association with clinical outcomes to anti-PD-1, and how their non-uniformgeographic distribution contributed to observed discrepancies between previously published cohorts. Theseresults have prompted follow up trials evaluating microbiome modulation in refractory ICI colitis and othercancers.To evaluate the additive role of TLR9 agonism to PD-1 blockade in melanoma, I conducted a phase IIneoadjuvant study of TLR9 agonist CMP-001 with PD-1 inhibitor nivolumab in high-risk resectable melanoma.Early results have been presented as Oral Presentations at the Society for Immunotherapy of Cancer (SITC)Annual Meetings in 2019 and 2020. We demonstrated that the neoadjuvant nivolumab/CMP-001 combinationproduced high pathologic response rates with evidence of immune activation peripherally and intra-tumorally.These results have prompted several follow-on studies.Separately, I have contributed to the development and implementation of the first-in-human studies of TIGITmAb (BMS-986207), Tim-3 mAb (TSR-022), GITR mAb (TRX-518), CTLA-4 NF (BMS-986218), anti-IL-8(BMS-986253), and prostaglandin E2 (PGE2) receptor 4 (EP4) antagonist (BMS-986310).My research interests lie in translational cancer immunotherapy and designing novel clinical trials to addressimportant scientific questions. My goal is to have a career as a physician-scientist with a clinical practicefocusing on melanoma and a translational career centered on designing early-phase clinical trials based on animproved understanding of tumor immunobiology and host-tumor-microenvironment interactions. In summary, Ihave a demonstrated record of accomplished and productive research projects in an area of high relevance fora population with a highly lethal disease.