Molecular and immune drivers of immunotherapy responsiveness in prostate cancer

前列腺癌免疫治疗反应的分子和免疫驱动因素

基本信息

批准号：
9788321
负责人：
Lawrence Fong
金额：
$ 84.29万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-19 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9788321
关键词：
Address Antigens Architecture Biological Biological Models California Cancer Patient Cell Communication Cell physiology Cells Chromatin Chromatin Remodeling Factor Clinical Combination immunotherapy Community Networks Cytotoxic Chemotherapy DNA Damage DNA Repair Data Defect Disease Drug Targeting Epigenetic Process Genes Immune Immune checkpoint inhibitor Immune response Immune system Immunogenomics Immunologics Immunooncology Immunosuppressive Agents Immunotherapeutic agent Immunotherapy Institutes International Investigation Malignant Neoplasms Malignant neoplasm of prostate Maps Mediating Metastatic Prostate Cancer Microsatellite Instability Mismatch Repair Molecular Mutation PD-1 blockade Patients Phase Phenotype Population Pre-Clinical Model Process Property Research Personnel Resistance Resources Sampling San Francisco Scientist Solid Neoplasm Somatic Mutation T-Lymphocyte Testing Therapeutic Translations Tumor-infiltrating immune cells Universities Work anti-PD-1 anti-PD1 therapy anti-tumor immune response base cancer genomics cancer immunotherapy castration resistant prostate cancer chromatin remodeling cohort cytotoxic experience hormone therapy immune checkpoint immune checkpoint blockade immunotherapy clinical trials improved outcome member men mouse model multidisciplinary mutant neoplastic cell novel pre-clinical programs prostate cancer cell prostate cancer model response single cell analysis treatment strategy tumor

项目摘要

PROJECT SUMMARY Despite recent advances in treatment, metastatic castration resistant prostate cancer (mCRPC) remains incurable, and approximately 30,000 men die of this disease yearly. Advances in immunotherapy with drugs targeting immune checkpoints have raised hopes that these agents will improve outcomes for mCRPC patients. While initial studies of immune checkpoint blockade have been unsuccessful, emerging evidence suggests a subset of prostate cancer (PCa) patients can respond, although the mechanisms of PCa immunotherapy response and resistance are incompletely characterized. Work in other immunotherapy responsive malignancies has found several predictive immune and tumor-intrinsic properties that contribute to response, but the extent to which these (or other) features are operant in PCa is largely unknown. For example, we recently identified mutations in a chromatin remodeling complex that mediates immunotherapy response through T cell interactions in solid tumors, and in parallel discovered a previously unknown PCa genomic subclass defined by mutations in these same chromatin remodelers. These findings indicate that tumor-intrinsic epigenetic dysregulation may also interact with the immune system to modulate PCa immunotherapy responsiveness. The overarching hypothesis of this project is that multiple immune and tumor- intrinsic properties mediate PCa interactions with the immune system, and these interactions can be modified through selective targeting in combination with checkpoint blockade to expand the therapeutic potential of immunotherapy in PCa. We will leverage our team's deep experience in clinically grounded molecular characterization and preclinical models that can test immunotherapy combinations in PCa to define the processes that govern the immunotherapy landscape in PCa. The proposed specific aims are: 1) Define the systemic and infiltrating immune states in PCa associated with clinical response to checkpoint blockade; 2) Establish the immunologic impact of chromatin dysregulation and inhibition in PCa; and 3) Determine the impact of existing DNA damaging agents for sensitizing PCa to PD-1 blockade. This proposal leverages the extensive, novel, and complementary resources at both Dana-Farber/Broad Institute and University of California, San Francisco, led by highly collaborative investigators and an international scientific team, to address the hypotheses outlined herein. Through a combination of functional, molecular, and clinical approaches inherent in these studies, our team is poised to identify mCRPC cohorts that may benefit from this treatment paradigm, determine strategies to augment the use of checkpoint inhibitors in this disease, and mechanistically define the immune and tumor-intrinsic defects that drive immunoresistance in PCa. Broadly, this project will provide a unique approach for the Immuno-Oncology Translation Network (IOTN) community and enable discovery of anti-cancer immunotherapies strategies for PCa that may have larger relevance across the IOTN network and collaborating members of the Cancer Immunotherapy Consortium.

项目概要尽管最近治疗取得进展，转移性去势抵抗性前列腺癌（mCRPC）仍然存在这种疾病无法治愈，每年约有 30,000 人死于这种疾病。药物免疫治疗的进展针对免疫检查点的药物引发了人们的希望，即这些药物将改善 mCRPC 的结果患者。虽然免疫检查点封锁的初步研究并不成功，但新的证据表明一部分前列腺癌 (PCa) 患者可以做出反应，尽管 PCa 的机制免疫治疗反应和耐药性的特征不完全。从事其他免疫治疗工作反应性恶性肿瘤已经发现了一些预测性免疫和肿瘤内在特性，这些特性有助于反应，但这些（或其他）特征在 PCa 中起作用的程度很大程度上未知。为了例如，我们最近发现了介导免疫治疗的染色质重塑复合物中的突变通过实体瘤中 T 细胞相互作用产生的反应，同时发现了一种以前未知的 PCa 由这些相同染色质重塑者中的突变定义的基因组亚类。这些发现表明肿瘤内在的表观遗传失调也可能与免疫系统相互作用来调节 PCa 免疫治疗反应性。该项目的总体假设是多重免疫和肿瘤- 内在特性介导 PCa 与免疫系统的相互作用，并且这些相互作用可以被修改通过选择性靶向结合检查点封锁来扩大治疗潜力 PCa 的免疫治疗。我们将利用我们团队在临床基础分子方面的丰富经验表征和临床前模型，可以测试 PCa 中的免疫治疗组合，以确定控制 PCa 免疫治疗前景的过程。提议的具体目标是： 1) 定义 PCa 的全身和浸润免疫状态与检查点封锁的临床反应相关； 2）确定 PCa 中染色质失调和抑制的免疫学影响； 3) 确定现有 DNA 损伤剂对 PCa 对 PD-1 阻断敏感的影响。该提案利用了丹娜法伯/博德研究所和大学提供广泛、新颖且互补的资源加利福尼亚州、旧金山，由高度合作的研究人员和国际科学团队领导，解决本文概述的假设。通过功能、分子和临床的结合这些研究中固有的方法，我们的团队准备确定可能从中受益的 mCRPC 队列治疗范例，确定增加检查点抑制剂在这种疾病中的使用的策略，以及从机制上定义导致 PCa 免疫抵抗的免疫和肿瘤内在缺陷。广义上来说，该项目将为免疫肿瘤学翻译网络（IOTN）社区提供独特的方法并能够发现可能具有更大相关性的前列腺癌抗癌免疫疗法策略整个 IOTN 网络和癌症免疫治疗联盟的合作成员。