Defining neoantigen immunodominance for antigen selection and biomarker discovery in human pancreatic cancer immunotherapy

项目摘要 检查点阻断免疫疗法在治疗难治性癌症中诱导了显著的反应， 靶向由癌症特异性突变编码的新抗原。新抗原负荷预测免疫功能 响应，验证抗原鉴定作为生物标志物发现的合理策略。胰腺 然而，腺癌（PDAC）已经显示出对检查点阻断免疫疗法的有限功效， 推测新抗原缺乏。然而，在PDAC中缺乏系统的抗原发现。 3%的PDAC患者存活> 5年（长期存活者）。由于T细胞免疫可能解释了这种极端 结果，它们代表了深度抗原发现的理想队列。利用基因组分子和细胞 免疫分析、计算进化建模和新抗原发现，在这些罕见的长期 存活者（n=82），我们发现新抗原的质量，而不是数量，是生存的预后， 长期存活者表现出持久的新抗原特异性T细胞免疫。这项研究的科学目的 建议是解决转化这些发现所必需的问题- 1）是否有阶段和治疗- 特异性新抗原异质性，2）在外周血中能否鉴定新抗原，和3）能否 新抗原质量预测对免疫疗法的应答。翻译的目的是开发新的组织 和基于血液的生物标志物，用于免疫治疗的合理患者和靶点选择。 该提案利用了几种非常独特的组织收集策略- a）腹腔镜多部位活检， 鉴定阶段特异性异质性，B）化疗前和化疗后的系列评估， 调节，和c）评估作为大的免疫调节系统的预测性生物标志物的新抗原质量， PDAC试验。这一举措还将首次开发识别循环中新抗原的能力， 外泌体用于基于血液的生物标志物评估。研究方法采用下一代 测序、转录谱分析、计算生物物理建模、克隆型T细胞谱分析、新抗原 发现和功能评估，以评估预后，预测和治疗潜力， 新抗原该团队由世界级的专家初级和高级调查员组成， 纪念斯隆凯特琳癌症中心，迈耶癌症中心在威尔高度相关的学科 康奈尔医学中心、西奈山伊坎医学院蒂施癌症研究所和该研究所 高等研究这一举措与开发新型生物标志物的主要目标直接相关， T细胞抗原靶点在PDAC免疫治疗中的成功应用。

PROJECT SUMMARY Checkpoint blockade immunotherapy has induced dramatic responses in treatment refractory cancers by targeting neoantigens encoded by cancer-specific mutations. Neoantigen load predicts immunotherapeutic response, validating antigen identification as a rational strategy of biomarker discovery. Pancreatic adenocarcinoma (PDAC) however has shown limited efficacy to checkpoint blockade immunotherapy due to presumed neoantigen paucity. However, systematic antigen discovery in PDAC is lacking. 3% of PDAC patients survive > 5 years (long term survivors). As T cell immunity may explain this extreme outcome, they represent the ideal cohort for deep antigen discovery. Using genomic, molecular, and cellular immunoprofiling, computational evolutionary modeling, and neoantigen discovery in these rare long term survivors (n=82), we have discovered that neoantigen quality, but not quantity, is prognostic of survival, and that long term survivors evidence lasting neoantigen-specific T cell immunity. The scientific objectives of this proposal are to address questions essential to translate these findings - 1) is there stage and treatment- specific neoantigen heterogeneity, 2) can neoantigens be identified in the peripheral blood, and 3) can neoantigen quality predict response to immunotherapy. The translational objective is to develop novel tissue and blood-based biomarkers for rational patient and target selection for immunotherapy. The proposal utilizes several highly unique tissue collection strategies – a) laparoscopic multi-site biopsies to identify stage-specific heterogeneity, b) serial pre- and post-chemotherapy assessment for treatment-specific modulation, and c) evaluation of neoantigen quality as a predictive biomarker on a large, immunotherapeutic PDAC trial. This initiative will also for the first time develop the ability to identify neoantigens in circulating exosomes for blood-based biomarker assessment. The research methodology employs next generation sequencing, transcriptional profiling, computational biophysical modeling, clonotypic T cell profiling, neoantigen discovery, and functional assessments to evaluate the prognostic, predictive, and therapeutic potential of neoantigens. The team comprises of world-class expert junior and senior investigators in a broad range of highly relevant disciplines from Memorial Sloan Kettering Cancer Center, Meyer Cancer Center at the Weill Cornell Medical Center, Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and the Institute for Advanced Study. This initiative is directly relevant to the primary objective to develop novel biomarkers and T cell antigenic targets for the successful application of immunotherapy in PDAC.