Targeting autophagy to enhance immune checkpoint inhibition

靶向自噬增强免疫检查点抑制

基本信息

批准号：
10480852
负责人：
RAVI K AMARAVADI
金额：
$ 44.6万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-03 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10480852
关键词：
Address Affect Antineoplastic Agents Attention Autophagocytosis BRAF gene Biological Markers Biopsy Biotechnology CD8-Positive T-Lymphocytes CD8B1 gene Cells Chemicals Chloroquine Clinic Clinical Clinical Research Clinical Trials Collaborations Data Dendritic Cells Development Effectiveness Future Generations Genetic Glean Goals Histologic Hydroxychloroquine Imaging technology Immune Immune checkpoint inhibitor Immunity Immunologic Tests Immunotherapeutic agent Immunotherapy Impairment In Vitro Institution Interferon Activation Interferons Knockout Mice Knowledge Lead MEK inhibition Macrophage Activation Malignant Neoplasms Measures Modeling Molecular Target Mus Myeloid Cells Myeloproliferative disease Nivolumab Pathway interactions Patients Phase I/II Trial Phenotype Plasma Positron-Emission Tomography Pre-Clinical Model Proteome Refractory Regimen Resistance Safety Sampling Series Signal Transduction Skin Cancer Specificity Systems Biology T-Lymphocyte Techniques Testing Treatment Protocols Tumor-associated macrophages Tumor-infiltrating immune cells Work anti-CTLA4 anti-PD-1 anti-PD1 antibodies cancer cell cell type checkpoint inhibition chemotherapy clinical investigation clinically relevant drug development genetic analysis improved in vivo inhibition of autophagy inhibitor ipilimumab lysosomal proteins macrophage melanoma mouse model mutant neoplastic cell new therapeutic target next generation novel novel strategies novel therapeutic intervention pre-clinical preclinical study preclinical trial randomized trial resistance mechanism response response biomarker targeted treatment therapy resistant thioesterase PPT1 gene product tumor tumor growth tumor microenvironment

项目摘要

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.

项目摘要 - 项目2 一种可以克服对免疫抑制（ICI）抵抗力的新方法是对 IV期黑色素瘤患者。该项目的总体目标是确定ICI是否与自噬结合抑制可以解决这种未满足的需求。自噬是化学疗法的关键抗药性机制，并针对治疗。最近，我们的工作和他人的工作已经实施了自噬作为一种抵抗机制免疫疗法。这引发了许多问题，即哪种是针对自噬的最佳方法哪种细胞类型对于靶向自噬在肿瘤微环境中最重要。这个项目将利用与开发下一代的新兴生物技术公司的深入合作前往诊所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总体假设，即溶酶体自噬抑制会导致聚焦的细胞途径扰动在提高ICI效率的癌细胞和免疫细胞中：特定目标1将确定机制新型临床级自噬抑制剂通过它调节ICI期间的肿瘤免疫相互作用对髓样，肿瘤，T细胞和其他免疫细胞表型的影响。我们将比较每种在临床相关的小鼠模型中，抑制剂增加了抗PD-1和抗CTLA-4 AB的抑制剂。我们将集中精力在PPT1上，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，也是令人兴奋的癌症药物开发目标。我们将利用我们的新颖有条件的PPT1 KO小鼠模型，以比较ICI与PPT1 KO在肿瘤细胞，树突状细胞和髓样中的效果细胞，并将遗传抑制与化学PPT1对黑色素瘤肿瘤生长的抑制作用。在特定目标2中将确定患者中TME免疫元素的变化以及与联合处理的临床前模型的变化 ICI和自噬抑制作用。我们将进行极限黑色素瘤试验，这是Nivolumab的自适应I/II期试验 IV期黑色素瘤患者中的 + HCQ和Nivolumab + ipilimumab + HCQ。新颖的宠物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+分析相关临床反应。在相关的临床前小鼠研究中，我们将使用公正的方法来实现早期用ICI和HCQ或ICI和DC661治疗的黑色素瘤肿瘤变化的综合视图反应和阻力。影响：我们的研究将确定自噬抑制剂调节的机制 TME在提供临床前原理时使用新颖的临床试验来推出下一代临床试验在ICI组合方案中，自噬抑制剂比HCQ具有更大的潜力和特异性。我们的临床试验将提供宝贵的安全性和临床活动数据，还将指导发展更多潜力和特定的自噬抑制剂。