Predicting and profiling long-term survival after immune checkpoint inhibition

项目摘要 免疫检查点抑制剂，特别是抗PD-1/PD-L1(程序性细胞死亡-1/配体)，代表一种 对许多癌症具有临床疗效的新兴和新的治疗类别。因此，将特征描述为 预测应答、治疗中的免疫变化和长期临床结果是 庞大且不断增长的人口。目前，我们仍然很大程度上无法预测个别患者受益于 这些特工。使用接受抗PD-1/PD-L1治疗的患者的治疗前样本，我们发现 主要组织相容性II类(MHC-II)的表达与治疗反应密切相关，也与 CD_4、CD_8 T细胞浸润。细胞系研究还表明，MHC-II的表达也与 支持免疫的基因特征，包括“T细胞受体信号传递”、“PD-1反应体”等途径，以及 “同种异体移植排斥反应”在更大的队列中，我们将使用定性和定量的免疫组织化学方法。 验证并建立MHC-II表达对抗PD-1/PD-L1(目的1)有利的预测价值。我们会 此外，还要评估普通黑色素瘤治疗药物在体外是否可以诱导MHC-II。接下来，我们将 利用尖端的多重质量细胞术来表征进化中的抗肿瘤免疫反应 由抗PD-1释放。现有数据表明，在抗PD-1/PD-L1反应性肿瘤中，预先存在 存在通过阻断PD-1/PD-L1而释放的免疫应答。因此，我们假设 外周和肿瘤浸润性免疫细胞在治疗前和治疗后可能是不同的 响应者。为了实现对多个进化的免疫亚群的前所未有的纵向表征，我们 将对外周血进行高维多路质量细胞术分析(基线时获得，3 治疗后3周、12周、6个月)和肿瘤活检(基线和3周)(目标2)。最后，虽然 许多患者对抗PD-1/PD-L1有反应，其分子基础、发病率、发生时间和临床特征 获得性抵抗力的特征是完全没有特征的。此外，慢性和迟发性毒性的发生率 没有被探索过。我们计划收集大量人群的回顾性临床数据和肿瘤样本 患者有反应，然后进步，并探索长期幸存者接受治疗的毒性 抗PD-1/PD-L1(目标3)。这些研究与国际公认的导师和顾问一起， 和严格的培训计划，将提供开展独立研究的最佳条件 从事以病人为中心的高影响力研究。

Project Summary Immune checkpoint inhibitors, particularly anti-PD-1/PD-L1 (programmed cell death-1/ligand), represents an emerging and novel therapeutic class with clinical efficacy in many cancers. As such, characterizing features predictive of response, immune changes on therapy, and long-term clinical outcomes are critical objectives for a large and growing population. Currently, we remain largely unable to predict individual patient benefit from these agents. Using pre-treatment samples from patients who received anti-PD-1/PD-L1, we identified that expression of major histocompatibility class II (MHC-II) strongly correlated with response to therapy, as well as CD4 and CD8 T cell infiltration. Cell line studies also suggested that MHC-II expression also correlates with pro-immune gene signatures, including pathways such as “T cell receptor signaling”, “PD-1 reactome”, and “allograft rejection.” In a larger cohort, we will use qualitative and quantitative immunohistochemistry methods to verify and establish the predictive value of MHC-II expression on benefit to anti-PD-1/PD-L1 (Aim 1). We will also assess whether MHC-II may be induced by common melanoma therapeutics in vitro. Next, we will leverage cutting edge multiplexed mass cytometry to characterize the evolving anti-tumor immune response unleashed by anti-PD-1. Available data suggests that in anti-PD-1/PD-L1 responsive tumors, a pre-existing immune response exists that is released by the blockade of PD-1/PD-L1. As such, we hypothesize that peripheral and tumor infiltrating immune cells may be distinct prior to, and following treatment among treatment responders. To achieve unprecedented longitudinal characterization of multiple evolving immune subsets, we will perform high-dimensional multiplexed mass cytometry analysis on peripheral blood (obtained at baseline, 3 weeks, 12 weeks, 6 months after treatment) and tumor biopsies (baseline and 3 weeks) (Aim 2). Finally, while many patients respond to anti-PD-1/PD-L1, the molecular basis, incidence, timing, and clinical characteristics of acquired resistance are totally uncharacterized. Further, the incidence of chronic and delayed toxicities has not been explored. We plan to collect retrospective clinical data and tumor samples on a large population of patients who respond and then progress, and explore toxicities experienced by long-term survivors treated with anti-PD-1/PD-L1 (Aim 3). These studies, in conjunction with internationally recognized mentors and advisors, and a rigorous training plan, will provide the optimal conditions from which to develop an independent research career performing high-impact patient-oriented research.