Targeting autophagy to enhance immune checkpoint inhibition

项目摘要-项目2 一种新的方法可以克服对免疫检查点抑制(ICI)的抵抗，这是一种尚未得到满足的主要需求 IV期黑色素瘤患者。这个项目的总体目标是确定ICI与自噬是否相结合 抑制可以解决这种未得到满足的需求。自噬是化疗耐药和靶向耐药的关键机制 心理治疗。最近，我们的工作和其他人的工作表明，自噬是一种抵抗机制 免疫疗法。这引发了一些问题，即哪种方法是靶向自噬和在 在肿瘤微环境中靶向自噬最关键的是哪种细胞类型。这个项目将 利用与开发下一代产品的新兴生物技术公司的深度合作 正在走向临床的化学溶酶体和非溶酶体自噬抑制剂。以下目标将 测试我们的整体假设，即溶酶体自噬抑制会导致聚焦的细胞途径扰动 在增强ICI疗效的癌细胞和免疫细胞中：特异性靶点1将确定其机制 在ICI过程中，新的临床级自噬抑制剂通过哪些途径调节肿瘤-免疫相互作用，重点是 对髓系、肿瘤、T细胞和其他免疫细胞表型的影响。我们将比较其中每一个的能力 在临床相关的小鼠模型中增加联合抗PD-1和抗CTLA-4抗体的抑制剂。我们将专注于 在PPT1上，一种调节自噬的溶酶体硫酯酶，也是氯喹的主要分子靶标 衍生物，以及抗癌药物开发的一个令人兴奋的新目标。我们将使用我们的新的条件Ppt1 建立KO小鼠模型，比较ICI联合Ppt1 KO对肿瘤细胞、树突状细胞和髓系细胞的影响 细胞，并比较基因抑制和化学Ppt1对黑色素瘤肿瘤生长的抑制。《特定目标2》 将确定联合治疗患者和临床前模型的TME免疫图谱的变化 ICI和自噬抑制。我们将进行Limit黑色素瘤试验，这是nivolumab的适应性I/II期试验 IV期黑色素瘤患者+hcq和nivolumab+ipilimumab+hcq。新型PET成像技术 将用于跟踪肿瘤中的CD8+T细胞，并将CD8+信号与组织学CD8+分析和 临床反应。在相关的小鼠临床前研究中，我们将使用公正的方法来实现 ICI与HCQ或ICI与DC661联合治疗黑色素瘤早期变化综述 反应和抵抗。影响：我们的研究将确定自噬抑制物调节的机制 TME在提供使用新技术启动下一代临床试验的临床前理论基础的同时 在ICI联合方案中，自噬抑制剂比HCQ更有效和更特异。我们的临床试验将提供 有价值的安全性和临床活动数据，也将指导开发更有效和更具体的 自噬抑制剂。

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.