Serial immunotherapy combination to modulate the tumor environment in patients with metastatic gastroesophageal cancer

项目摘要/摘要 开发有效的治疗方法是转移性肿瘤患者亟待满足的医疗需求 胃食管腺癌(MGEA)。免疫检查点抑制剂的出现，如抗- 程序性死亡(PD)-1抗体使某些癌症的治疗发生了革命性变化，但仅对 少数GEA患者。为了将这一益处扩大到更多的患者，需要联合治疗。 大多数研究表明GEA联合免疫治疗在阻断PD-1的同时具有细胞毒作用 治疗，尽管细胞毒剂可能杀死一些由PD-1激活的T细胞 封锁，正如我们小组和其他人所表明的那样。我们的长期目标是开发免疫疗法组合 通过合理排序免疫疗法和其他抗癌药物来避免这个问题 增强肿瘤杀伤力，提高患者存活率。根据我们的初步数据，我们假设 抗PD-1系列联合免疫治疗和免疫调节抗血管生成治疗 按预定顺序进行化疗可显著改善临床结果。 随着免疫抑制肿瘤微环境的破坏和抗肿瘤系统的促进 免疫反应。为了验证这一假设，我们将进行第二阶段试验，以确定治疗 系列联合免疫治疗的疗效及其对局部和全身免疫反应的影响 在接受mGEA治疗的患者中，通过以下具体目标：目标1将确定其治疗效果 转移性GEA患者的系列联合免疫治疗。AIM 2将询问患者样本 从父母试验中纵向收集，以确定系列免疫疗法对 肿瘤环境中的免疫抑制、抗肿瘤和血管生成成分，包括肿瘤- 相关的局部和全身免疫反应。我们的预期结果是显示出改善的临床疗效 使用一种创新的免疫疗法组合，其中PD-1阻断剂以预定的顺序输送 并获得关于这一系列免疫治疗方法对肿瘤相关局部和 MGEA患者的全身免疫反应。总而言之，这些新的概念验证数据是 预计将为未来最终临床试验的设计提供信息，这些试验可以提高慢性阻塞性肺疾病患者的生存率 免疫治疗耐药的转移性GEA。

PROJECT SUMMARY/ABSTRACT Development of effective therapies is an urgent unmet medical need for patients with metastatic gastroesophageal adenocarcinoma (mGEA). The advent of immune checkpoint inhibitors such as anti- programmed death (PD)-1 antibodies has revolutionized treatment of some cancers but benefits only a minority of patients with GEA. Combination approaches are required to extend this benefit to more patients. Most studies of immunotherapy combinations in GEA initiate PD-1 blockade at the same time as cytotoxic therapy despite the possibility that cytotoxic agents may kill some of the very T cells invigorated by PD-1 blockade, as our group and others have shown. Our long-term goal is to develop immunotherapy combinations that avoid this problem through rational sequencing of immunotherapy with other anti-cancer agents to enhance tumor destruction and improve patient survival. Based on our preliminary data, we hypothesize that serial combination immunotherapy utilizing anti-PD-1 and anti-angiogenesis therapy with immunomodulatory chemotherapy in a predefined sequence leads to meaningful improvements in clinical outcomes in association with disruption of the immunosuppressive tumor microenvironment and promotion of antitumor systemic immune responses. To test this hypothesis, we will perform a phase II trial to determine the therapeutic efficacy of serial combination immunotherapy and examine its impact on local and systemic immune responses in patients with mGEA through the following specific aims: Aim 1 will determine the therapeutic efficacy of serial combination immunotherapy in patients with metastatic GEA. Aim 2 will interrogate patient samples collected longitudinally from the parent trial to identify the impact of serial immunotherapy on immunosuppressive, antitumor, and angiogenic components within the tumor environment, including tumor- related local and systemic immune responses. Our expected outcomes are to show improved clinical efficacy using an innovative immunotherapy combination in which PD-1 blockade is delivered in a predefined sequence and to gain critical knowledge on the impact of this serial immunotherapy approach on tumor-related local and systemic immune responses in patients with mGEA patients. Together, these new proof-of-concept data are expected to inform the design of future definitive clinical trials that can improve the survival of patients with immunotherapy-resistant metastatic GEA.