Research Project
10268745
Project Summary ? Project 2 A new approach that can overcome resistance to immune checkpoint inhibition (ICI) is a major unmet need for Stage IV melanoma patients. The overall goal of this project is to determine if combined ICI with autophagy inhibition can address this unmet need. Autophagy is a key resistance mechanism to chemotherapy and targeted therapy. More recently our work and the work of others has implicated autophagy as a resistance mechanism to immunotherapy. This raises a number of questions about which is the best approach to target autophagy and in which cell types is it most critical to target autophagy within the tumor microenvironment. This project will leverage deep collaborations with emerging biotechnology companies that have developed next generation chemical lysosomal and non-lysosomal autophagy inhibitors that are headed to the clinic. The following aims will test our overall hypothesis that lysosomal autophagy inhibition results in focused cellular pathway perturbations in cancer cells and immune cells that enhance the efficacy of ICI: Specific Aim 1 will determine the mechanism by which novel clinical grade autophagy inhibitors modulate tumor-immune interactions during ICI, focusing on effects on myeloid, tumor, T cell, and other immune cell phenotypes. We will compare the ability of each of these inhibitors to augment combined anti-PD-1 and anti CTLA-4 Ab in clinically relevant mouse models. We will focus on PPT1, a lysosomal thioesterase that regulates autophagy, and the major molecular target of chloroquine derivatives, and an exciting new target for cancer drug development. We will utilize our novel conditional Ppt1 KO mouse model, to compare the effects of ICI combined with Ppt1 KO in tumor cells, dendritic cells, and myeloid cells, and compare genetic inhibition to chemical Ppt1 inhibition on melanoma tumor growth. In Specific Aim 2 will determine changes in immunoprofiles of the TME in patients and preclinical models treated with combined ICI and autophagy inhibition. We will conduct the LIMIT melanoma trial, an adaptive phase I/II trial of nivolumab + HCQ and nivolumab + ipilimumab + HCQ in Stage IV melanoma patients. Novel PET imaging technologies will be used to track CD8+ T-cells in tumors and correlate CD8+ signal with histological CD8+ analysis and clinical response. In related pre-clinical mouse studies, we will use unbiased approaches to achieve a comprehensive view of changes in melanoma tumors treated with ICI and HCQ or ICI and DC661 during early response and resistance. Impact: Our study will identify the mechanism by which autophagy inhibitors modulate the TME while providing the preclinical rationale for launching next generation clinical trials using novel autophagy inhibitors more potent and specific than HCQ in ICI combination regimens. Our clinical trial will provide valuable safety and clinical activity data that will also guide the development of more potent and specific autophagy inhibitors.
