Project 2: Optimal Targeting of the PD-1/PD-L1 Pathway in MRCC

Summary: Anti-PD-1-based therapies have transformed the management of advanced renal cell carcinoma (RCC), leading to durable responses in a subset of patients. Despite this progress, the optimal therapeutic strategy (anti-PD-1 monotherapy versus dual checkpoint inhibition and dual checkpoint inhibition versus VEGF and PD-1 inhibition) for individual patients remains unclear, and too many patients still do not receive durable benefit from any of the PD-1 blockade-based therapies. Moving forward, the critical challenges are (i) how to best match a patient to an immunotherapy regimen, and (ii) understanding the key drivers and resistors of anti-RCC immunity following PD-1 blockade. Our unique access to a rich collection of samples from several front-line PD-1- blockade-based clinical trials and our comprehensive immunopathology and immunogenomics tool- kit for deeply dissecting the biologic features tumor cells and the immune microenvironment, uniquely position our group to address these challenges. To achieve the next paradigm shift in the treatment of patients with RCC, we hypothesize that an improved understanding of the expression state of RCC cells and their immune microenvironment at baseline provides critical information that will uncover targets for novel therapies and will rationally guide PD-1 blockade-based combinatorial therapy. We aim to clarify first-line therapy decisions by developing biomarkers for durable benefit from anti-PD-1 monotherapy, nivolumab/ipilimumab and axitinib/ pembrolizumab combination therapy using existing tissue collections, and then explore/confirm the value of these markers in the context of prospective phase III trials comparing the nivolumab/ipilimumab combination to either nivolumab monotherapy or axitinib/pembrolizumab. Ultimately, our efforts to establish a predictive model of durable benefit will help determine the appropriate RCC population to receive PD-1/CTLA-4 or PD-1/VEGF blockade, as well as unveil those patients who receive equal benefit from anti-PD-1 monotherapy or who require a different therapeutic approach. Moreover, we will use complementary analyses across patient samples to comprehensively characterize immune cell composition and functional state, determine target tumor antigens, and specific TCRs that mediate an effective anti-tumor response in RCC with the goal of ultimately developing novel immunotherapy approaches that enhance or induce specific and effective anti-tumor immunity. This work has the potential to optimize the application of currently effective anti-PD-1-based therapies for patients with advanced RCC and to provide new and effective immunotherapy approaches for those destined to not benefit optimally from current regimens.