Overcoming resistance to anti-PD1 immunotherapy

克服抗 PD1 免疫疗法的耐药性

• 批准号: 10547757
• 负责人: THOMAS F GAJEWSKI
• 金额: $ 92.71万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-07 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547757
• 关键词: Cancer Patient; Clinical; Combination immunotherapy; Data; Dimensions; Exclusion; Funding; Genetic Polymorphism; Genomics; Goals; Immunotherapy; Molecular; Monoclonal Antibodies; Outcome; Output; Patient-Focused Outcomes; Patients; Resistance; T cell response; T-Lymphocyte; T-cell inflamed; The Cancer Genome Atlas; Translational Research; Work; anti-PD-1; anti-PD1 therapy; cancer immunotherapy; cancer type; clinical efficacy; genomic data; gut microbiota; melanoma; neoplastic cell; novel; novel therapeutic intervention; patient subsets; predictive marker; response; response biomarker; translational approach; tumor; tumor microenvironment

ABSTRACT Novel immunotherapies for cancer are having a major clinical impact, in particular anti-PD-1 mAbs. However, the mechanisms that explain why a subset of patients responds to these therapies while other patients do not remain incompletely understood. Our preliminary data suggest that a baseline T cell-inflamed tumor microenvironment may be a predictive biomarker for response to multiple immunotherapies. Combination immunotherapies may push clinical efficacy in this subset of patients further. Our over-arching hypothesis is that germline polymorphisms in the host, genomic features of the tumor cells, and the composition of intestinal microbiota profoundly influence the extent of a spontaneous T cell response against a patient's tumor, which in turn will determine the likelihood of response to immunotherapy. Identifying molecular mechanisms for T cell exclusion should point towards new therapeutic interventions that will expand the fraction of patients responding to anti-PD-1- based immunotherapies. While our work to date has focused on melanoma, recent TCGA analysis has indicated that many of the same principles apply to multiple additional cancer types. Thus, a major goal of the proposed funding period will be to broaden our translational research strategy to encompass patients with all cancer types being treated with anti-PD-1- based immunotherapies. The output of this work is therefore anticipated to have profound impact on cancer patient outcomes overall.

抽象的 癌症的新型免疫疗法具有重大的临床影响，特别是抗PD-1 mabs。但是，解释了为什么一部分患者对此做出反应的机制 疗法虽然其他患者尚未完全了解。我们的初步数据 表明基线T细胞增添了肿瘤微环境可能是一种预测性生物标志物 以应对多种免疫疗法。结合免疫疗法可能会推动临床 这一子集进一步的功效。我们的整理假设是种系 宿主中的多态性，肿瘤细胞的基因组特征和组成 肠道菌群深刻影响自发T细胞反应的程度 反对患者的肿瘤，这反过来决定了 免疫疗法。识别T细胞排除的分子机制应指向 新的治疗性干预措施将扩大对抗PD-1-响应的患者的比例 基于免疫疗法。迄今为止，我们的工作重点是黑色素瘤，但最近的TCGA 分析表明，许多相同的原则适用于多种额外的癌症 类型。因此，拟议的融资期的主要目标是扩大我们的翻译 研究策略涵盖了用抗PD-1-治疗的所有癌症类型的患者 基于免疫疗法。因此，预计这项工作的输出将具有深刻的 总体上对癌症患者结局的影响。