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

项目总结 检查点阻断免疫疗法在治疗难治性癌症方面产生了显著的反应 靶向由癌症特异性突变编码的新抗原。新抗原载量预测免疫治疗 应答，确认抗原鉴定是发现生物标记物的合理策略。胰腺 然而，腺癌(PDAC)对检查点阻断免疫治疗的疗效有限，原因是 推定为新抗原缺乏。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)。因为T细胞免疫可以解释这种极端 结果，他们代表了深入发现抗原的理想队列。使用基因组、分子和细胞 这些罕见的长期免疫分析、计算进化建模和新抗原发现 幸存者(n=82)，我们发现新抗原的质量，而不是数量，是生存的预后，并且 长期存活的人证明新抗原特异性T细胞免疫是持久的。它的科学目标是 提案旨在解决翻译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)在外周血中能识别出新抗原，3)能 新抗原质量可预测对免疫治疗的反应。翻译的目标是开发新的组织 以及合理选择患者和免疫治疗靶点的血液生物标记物。 该方案利用几种高度独特的组织收集策略-a)腹腔镜多部位活检以 确定特定阶段的异质性，b)针对特定治疗进行化疗前和化疗后的连续评估 调节，以及c)评估新抗原质量作为大型免疫治疗的预测生物标记物 PDAC试验。这一倡议还将首次发展识别循环中新抗原的能力。 外切体用于血液生物标记物的评估。研究方法采用新一代技术 测序、转录图谱、计算生物物理模型、克隆型T细胞图谱、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。该小组由世界级专家、初级和高级调查人员组成，范围广泛 来自纪念斯隆·凯特琳癌症中心、威尔迈耶癌症中心的高度相关的学科 康奈尔医学中心、西奈山伊坎医学院的Tisch癌症研究所和该研究所 为了进修。这一倡议与开发新的生物标记物和 T细胞抗原靶点为免疫治疗在PDAC中的成功应用奠定了基础。

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.