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Developing strategies to inhibit cancer immunotherapy-induced immune-related adverse events without impeding anti-tumor immunity

制定策略来抑制癌症免疫治疗引起的免疫相关不良事件而不妨碍抗肿瘤免疫

基本信息

批准号：
10090581
负责人：
Arabella Young
金额：
$ 12.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2021-11-30
项目状态：
已结题

项目摘要

Project Summary/Abstract Tumors elicit a range of suppressive mechanisms in order to evade the immune system. Many of these are targetable as evidenced by the great success of cancer immunotherapies that boost a patient's own immune response towards cancer. Often, targets for cancer immunotherapies represent pathways that at homeostasis protect against activation of an immune response towards self, limiting the development of autoimmune disease. Cancer patients treated with immune-potentiating therapies are exposed to significant risk of developing immune-related adverse events (irAEs). These irAEs have been reported in nearly every organ system, and in many cases represent non-resolving autoimmune side-effects that pose a significant impact due to their potential morbidity, mortality and associated healthcare costs. With a growing number of immunotherapies reaching clinical utility and increasing combination studies that may initiate more frequent and severe irAEs, understanding which therapeutic approaches provide improved tumor control with minimal side-effects is essential. In this study, by generating transplantable, syngeneic tumor cell lines in autoimmune- prone NOD mice, which develop autoimmune pathologies in response to cancer immunotherapies, we may begin to assess the interplay between irAEs and anti-tumor immunity. In-depth profiling of genetic, epigenetic and cellular mechanisms that separate anti-tumor immunity versus autoimmunity in response to cancer immunotherapies will be defined to better engineer therapeutic strategies that enhance the immune response towards tumor with limited impact towards self. Using NOD tumors resistant to clinically-approved cancer immunotherapies such as anti-PD-1 and anti-CTLA-4, combination therapeutic strategies that reinvigorate immune activation in the tumor microenvironment will be identified and the associated risk for precipitating irAEs determined. Together, these preclinical models provide a platform to assess safety profiles for cancer immunotherapies, identifying mechanisms to inhibit or avoid irAEs while preserving anti-tumor immunity. This research will be performed amongst world-class scientists and facilities at the University of California, San Francisco, this environment will foster expert training in the analysis of high-dimensional datasets generated from CyTOF and 10X single-cell RNA and TCR sequencing, an essential skill for delineating the complex mechanisms contributing to immune-mediated disease. Both my mentorship committee, led by Dr. Jeffrey Bluestone and expert collaborators will allow me to fulfil these research goals. Following, I will transition to an independent position establishing a research program that integrates the effect of multiple environmental factors, including microbiome, diet, age and stress, alongside autoimmune and anti-tumor immune responses to cancer immunotherapy using the NOD tumor models that have been developed, with the ultimate aim to improve safety, specificity and treatment efficacy for immunotherapy-treated cancer patients.

项目总结/摘要肿瘤引发一系列抑制机制以逃避免疫系统。其中许多是癌症免疫疗法的巨大成功证明了这一点，对癌症的反应。通常，癌症免疫疗法的靶点代表了处于稳态的途径，防止对自身的免疫反应的激活，限制自身免疫性疾病的发展疾病用免疫增强疗法治疗的癌症患者暴露于免疫缺陷的显著风险。发生免疫相关不良事件（irAE）。这些irAE几乎在所有器官中均有报告系统，并在许多情况下代表非解决自身免疫性副作用，造成显着影响由于其潜在的发病率、死亡率和相关的医疗费用。与越来越多的免疫疗法达到临床实用性，并增加可能启动更频繁的联合研究和严重irAE，了解哪些治疗方法可以改善肿瘤控制，副作用很重要。在这项研究中，通过产生可移植的，同源的肿瘤细胞系，在自身免疫- 易患NOD的小鼠，在对癌症免疫治疗的反应中发展出自身免疫性病理，我们可以开始评估irAE与抗肿瘤免疫之间的相互作用。深入剖析遗传、表观遗传以及区分抗肿瘤免疫和自身免疫的细胞机制免疫疗法将被定义为更好地设计增强免疫反应的治疗策略对自身影响有限。使用对临床批准的癌症具有抗性的NOD肿瘤免疫疗法如抗PD-1和抗CTLA-4，将识别肿瘤微环境中的免疫激活，并确定肿瘤微环境中的相关风险，确定irAE。总之，这些临床前模型提供了一个评估癌症安全性的平台。免疫疗法，鉴定抑制或避免irAE同时保留抗肿瘤免疫的机制。这这项研究将在加州大学旧金山分校的世界级科学家和设施中进行。弗朗西斯科，这种环境将促进专家培训，在分析高维数据集产生从CyTOF和10 X单细胞RNA和TCR测序，一个基本的技能，描绘复杂的导致免疫介导疾病的机制。我的导师委员会，由杰弗里博士领导 Bluestone和专家合作者将使我能够实现这些研究目标。接下来，我将过渡到独立的立场，建立一个研究计划，综合多种环境的影响，因素，包括微生物组，饮食，年龄和压力，以及自身免疫和抗肿瘤免疫反应使用已经开发的NOD肿瘤模型进行癌症免疫治疗，最终目的是提高免疫疗法治疗癌症患者的安全性、特异性和治疗功效。