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

项目总结/摘要 开发有效的治疗方法是转移性肺癌患者迫切的未满足的医疗需求。 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抗体已经彻底改变了一些癌症的治疗，但仅对 少数GEA患者。需要联合方法将这种益处扩展到更多患者。 大多数GEA免疫治疗组合的研究在细胞毒性治疗的同时启动PD-1阻断。 尽管细胞毒性药物可能会杀死一些被PD-1激活的T细胞， 封锁，正如我们集团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 通过免疫疗法与其他抗癌剂的合理排序来避免这个问题， 增强肿瘤破坏并提高患者存活率。根据我们的初步数据，我们假设， 利用抗PD-1的系列组合免疫疗法和具有免疫调节作用的抗血管生成疗法 预定顺序的化疗导致临床结果的有意义的改善， 破坏免疫抑制性肿瘤微环境并促进抗肿瘤系统性免疫抑制。 免疫反应。为了验证这一假设，我们将进行一项II期试验，以确定治疗 系列联合免疫治疗的有效性并检查其对局部和全身免疫应答的影响 在mGEA患者中，通过以下具体目标：目标1将确定 转移性GEA患者的系列联合免疫治疗。Aim 2将询问患者样本 从母试验中纵向收集，以确定系列免疫治疗对 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 使用创新的免疫疗法组合，其中PD-1阻断以预定义的顺序递送， 并获得关于这种系列免疫治疗方法对肿瘤相关局部和 mGEA患者的全身免疫应答。总之，这些新的概念验证数据是 预计将为未来确定性临床试验的设计提供信息，这些临床试验可以改善患者的生存率。 免疫治疗抗性转移性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.