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

连续免疫疗法组合调节转移性胃食管癌患者的肿瘤环境

• 批准号: 10320947
• 负责人: Harry H Yoon
• 金额: $ 63.93万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10320947
• 关键词: Address; Aftercare; Antibodies; Antineoplastic Agents; Biological; Biological Assay; Blood specimen; CD8-Positive T-Lymphocytes; Cancer Etiology; Cause of Death; Cessation of life; Clinical; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Cytometry; Cytotoxic Chemotherapy; Cytotoxic agent; Data; Development; Disease; Disease Progression; Distant Metastasis; Drug Efflux; Effectiveness; Environment; FOXP3 gene; Flow Cytometry; Future; Goals; Granzyme; Immune; Immune checkpoint inhibitor; Immune response; Immunotherapy; In complete remission; KDR gene; Knowledge; Lead; Malignant Neoplasms; Medical; Microanatomy; Minority; Outcome; Paclitaxel; Parents; Patients; Pharmaceutical Preparations; Pilot Projects; Regimen; Regulatory T-Lymphocyte; Research; Resistance; Sampling; Selection for Treatments; T-Lymphocyte; Testing; Time; Treatment Efficacy; Tumor Promotion; anti-tumor immune response; antiangiogenesis therapy; arm; base; bevacizumab; cancer therapy; chemotherapy; clinical efficacy; density; design; effective therapy; experimental arm; gastroesophageal adenocarcinoma; gastroesophageal cancer; immune activation; immunoregulation; improved; innovation; insight; novel; novel therapeutic intervention; pembrolizumab; phase II trial; preservation; primary endpoint; programmed cell death protein 1; response; taxane; tumor; tumor-immune system interactions

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.

项目摘要/摘要 开发有效疗法是转移性患者的紧急医疗需求 胃食管腺癌（MGEA）。免疫检查点抑制剂的出现，例如抗 程序性死亡（PD）-1抗体已彻底改变了对某些癌症的治疗，但仅受益于 少数GEA患者。需要使用组合方法将此益处扩展到更多的患者。 GEA中免疫疗法组合的大多数研究与细胞毒性同时启动PD-1封锁 治疗尽管有可能细胞毒性剂杀死PD-1激发的一些T细胞 封锁，正如我们的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 通过与其他抗癌药对免疫疗法进行合理测序来避免此问题 增强肿瘤破坏并改善患者的生存率。根据我们的初步数据，我们假设 使用抗PD-1和抗血管生成治疗的串行组合免疫疗法和免疫调节 预定义序列中的化学疗法会导致临床结局的有意义改善 随着免疫抑制性肿瘤微环境的破坏和抗肿瘤全身的促进 免疫反应。为了检验这一假设，我们将执行II期试验以确定治疗性 串行组合免疫疗法的功效并检查其对局部和全身免疫反应的影响 在通过以下特定目的的MGEA患者中：AIM 1将确定治疗功效 转移性GEA患者的串行组合免疫疗法。 AIM 2将询问患者样本 从父母试验中纵向收集，以确定连续免疫疗法对 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提高的临床功效 使用创新的免疫疗法组合，其中PD-1封锁以预定义的序列传递 并获得有关这种连续免疫疗法方法对肿瘤相关局部和 MGEA患者患者的全身免疫反应。这些新的概念证明数据是 有望告知未来确定临床试验的设计，该试验可以改善 免疫疗法的转移性GEA。