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：
10268745
负责人：
RAVI K AMARAVADI
金额：
$ 47.05万
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/10268745
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/antagonist 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.

项目总结 – 项目 2 一种可以克服免疫检查点抑制（ICI）耐药性的新方法是目前尚未满足的主要需求 IV 期黑色素瘤患者该项目的总体目标是确定 ICI 是否与自噬相结合。抑制可以解决这种未满足的需求，自噬是化疗和靶向的关键耐药机制。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。这引发了一些关于哪种是靶向自噬的最佳方法的问题。该项目将研究哪些细胞类型对于肿瘤微环境中的自噬最为关键。利用与开发下一代的新兴生物技术公司的深入合作即将进入临床的化学溶酶体和非溶酶体自噬抑制剂将实现以下目标。检验我们的总体假设，即溶酶体自噬抑制会导致集中的细胞途径扰动增强 ICI 功效的癌细胞和免疫细胞：具体目标 1 将确定机制新型临床级自噬抑制剂在 ICI 期间调节肿瘤免疫相互作用，重点关注对骨髓、肿瘤、T 细胞和其他免疫细胞表型的影响我们将比较每种细胞的能力。我们将重点关注在临床相关小鼠模型中增强联合抗 PD-1 和抗 CTLA-4 Ab 的抑制剂。 PPT1，一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，以及令人兴奋的癌症药物开发新目标，我们将利用我们的新型条件 Ppt1。 KO小鼠模型，比较ICI联合Ppt1 KO对肿瘤细胞、树突状细胞、骨髓细胞的影响细胞，并比较遗传抑制与化学 Ppt1 对黑色素瘤肿瘤生长的抑制。将确定接受联合治疗的患者和临床前模型中 TME 免疫特征的变化我们将进行 LIMIT 黑色素瘤试验，这是一项纳武单抗的适应性 I/II 期试验。 + HCQ 和纳武单抗 + 伊匹单抗 + HCQ 用于 IV 期黑色素瘤患者新型 PET 成像技术。将用于追踪肿瘤中的 CD8+ T 细胞，并将 CD8+ 信号与组织学 CD8+ 分析相关联，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使用 ICI 和 HCQ 或 ICI 和 DC661 治疗黑色素瘤肿瘤变化的综合视图影响：我们的研究将确定自噬抑制剂的调节机制。 TME，同时提供使用新型药物启动下一代临床试验的临床前基本原理我们的临床试验将提供比 HCQ 更有效、更特异的自噬抑制剂 ICI 联合治疗方案。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药物自噬抑制剂。