Immunobiology and Immune Therapy for Merkel Cell Carcinoma

University Of Washington, Seattle WA

Investigators

Linked publications & trials

Abstract

Summary - Overall: Immunobiology and Immune Therapy for Merkel Cell Carcinoma Our Seattle-based P01 team, with collaborators around the world, has played a leading role in characterizing the immune response against Merkel cell carcinoma (MCC), an often-lethal, polyomavirus-driven, skin cancer. We led clinical trials targeting immune pathways including PD-1 blockade that markedly improved the outlook for patients with this aggressive disease. Although nearly half of patients derive long-term benefit from PD-1 pathway blockade, there remains an unmet need to develop new approaches for PD-1 refractory patients. During the current funding period, our P01 team was highly productive, publishing 77 studies that collectively have been cited 1,858 times. Furthermore, our group’s contributions resulted in at least five changes to the National Comprehensive Cancer Network guidelines (with six more anticipated within the next 2-3 years) for the care of MCC patients, including studies supporting the approval of all three FDA-indicated treatments for MCC. This renewal seeks to improve our understanding of immune evasion mechanisms and identify therapeutically feasible approaches to reverse resistance to existing immunotherapies. Our team is uniquely positioned to address important immuno- oncology questions in the field because: 1) we have created unique immune tools to study T and B cell responses to Merkel cell polyomavirus (MCPyV)-induced MCC, and 2) our specimen and data repository provides access to clinically annotated biospecimens from hundreds of patients, including specimens from highly relevant clinical trials of patients who do and do not respond to immunotherapy. Project 1 will utilize a high-avidity anti-MCPyV T cell receptor with an activating “immune fusion protein” receptor (CD200R/CD28) to transduce patient cells and generate highly functional, MCPyV-specific T cells capable of overcoming HLA class I downregulation on MCC tumors. Biomarker studies will be conducted to determine the mechanisms involved in response or non-response to this cutting-edge approach. Project 2 will reveal mechanisms associated with response or resistance to PD-1 pathway blockade by studying pre- and post-immunotherapy biospecimens, including from multiple clinical trials that originated from this P01. These specimens will be used to identify clinically targetable aspects of the biology of tumor cells, T cells, and innate immune cells (including macrophages and dendritic cells) that affect the response to PD-1 blockade. Project 3 is poised to provide exciting insight into a persistent problem in the field of cancer immunology: how B cells interact with CD4 and CD8 T cells to combat cancer. We leverage expertise in identifying tumor-antigen specific B cells with the fact that MCPyV tumor antigens are shared among MCC patients. Excitingly, we found that MCPyV-specific B cells with germinal center features are highly predictive of patient survival. These studies will be enabled by an exciting new mouse model that is immune competent and the first to generate Merkel cell carcinomas via the MCPyV oncoproteins that drive human MCC. Leveraging these opportunities and resources, this uniquely qualified team will identify and validate actionable mechanisms of immune evasion that will improve the management of MCC and immunogenic cancers more broadly.