Understand & overcome resistance to PD-1

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Abstract

Summary, Project 2: Characterizing and overcoming failure to respond to PD-1 blockade therapy Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer caused by the Merkel cell polyomavirus (MCPyV) in 80% of cases or by UV-induced mutations. MCPyV T-antigen oncoproteins are persistently expressed in virus-positive MCC (VP-MCC), while high numbers of UV-induced neoantigens are detected in virus-negative MCC (VN-MCC), meaning both MCC subsets harbor immunogenic epitopes. Based on our early studies of the immune response in MCC, our Seattle team led multiple clinical trials of PD-1/PD-L1 blockade therapy that changed the standard of care for this cancer. PD-1 blockade has yielded high response rates (~55%) in MCC as compared with other solid tumors, and markedly improved outcomes compared to cytotoxic chemotherapy, the only prior option for advanced MCC. While many patients derive durable benefit, roughly half do not respond (primary resistance), and initial responders often develop acquired resistance. In the current funding period, Project 2 contributed to 40 publications that were cited 1,317 times and led to multiple changes in MCC management guidelines. Our Seattle team played leadership roles in trials of PD-1/PD- L1 therapy resulting in all three FDA-approvals for MCC. Using NIH support, we developed immune tools to track and study MCPyV-specific T cells. These reagents allowed us to reveal a strong association between the frequency of MCPyV-specific CD8 T cells in blood and response to anti-PD-1, across two independent clinical trial discovery cohorts. In Aim 1, we propose to further test and validate the number and cell surface characteristics of circulating cancer-specific T cells as putative biomarkers of immunotherapy response. These approaches could provide therapeutic guidance for patients who do not respond to immunotherapy and enable more accurate assessment of the immunogenicity of clinical trial agents. Aim 2 focuses on augmentation of adaptive immunity against MCC via clinical targeting of immune evasion (i.e., triple checkpoint blockade) or via a cell cycle checkpoint (ATR inhibition) in advanced, PD-1 refractory disease. Aim 3 will build upon our previous findings to identify potentially targetable innate immune mechanisms that correlate with poor outcomes in patients receiving PD-1 therapy. This Project will be greatly enabled by our recent P01-funded progress in identifying biomarkers and immune evasion mechanisms. These exciting findings are now being translated into several relevant clinical trials funded by sources beyond this proposal. These trials will provide valuable samples to reveal mechanisms of response and evasion that have direct relevance to immunotherapy of more common immunogenic cancers. This proposal will thus address the most pressing needs in our field: to understand mechanisms of immune evasion relevant to resistance to PD-1 blockade, to develop clinically useful biomarkers predictive of response, and to identify effective approaches to overcome resistance to available immune therapies.