Pilot Project 1: Combination of Viroimmunotherapy and Microbiota Modulation to Treat Gastric Cancer

试点项目 1：病毒免疫疗法与微生物群调节相结合治疗胃癌

• 批准号: 10021569
• 负责人: FILIPA GODOY-VITORINO
• 金额: $ 12.6万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10021569
• 关键词: Address; African American; Antigens; Antitumor Response; Asians; Bacteria; Biological Markers; Brain Neoplasms; Breast; CD8B1 gene; Cancer Center; Cancer Etiology; Cell Line; Cells; Chemotherapy and/or radiation; Clinical; Clinical Data; Clinical Trials; Communities; Coupled; Data; Doctor of Medicine; Effectiveness; Exhibits; Funding; Generations; Germ-Free; Glioblastoma; Gnotobiotic; Hispanics; Human; Immune; Immunocompetent; Immunomodulators; Immunotherapy; In Vitro; Incidence; Infection; Infiltration; Inflammatory; Injections; Laboratories; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Mus; Not Hispanic or Latino; OX40; Oncolytic; Operative Surgical Procedures; Organoids; Outcome; Pacific Island Americans; Pathway interactions; Patients; Phase I Clinical Trials; Pilot Projects; Play; Population; Positioning Attribute; Property; Public Health; Puerto Rico; Radiation therapy; Recurrence; Role; Solid Neoplasm; Stomach; Survival Rate; T-Cell Receptor; T-Lymphocyte; TNFSF4 gene; Testing; Therapeutic Intervention; Translating; Translational Research; Translations; Tumor Necrosis Factor Receptor; Universities; Virotherapy; Virus; adenoviral-mediated; anti-PD-L1; anti-cancer; anti-tumor immune response; anticancer research; base; cancer initiation; career; clinical application; disparity reduction; experimental study; fecal transplantation; first-in-human; gut microbiome; gut microbiota; high risk; immune checkpoint; immunological synapse; immunotherapeutic virotherapy; improved; in vivo; malignant stomach neoplasm; member; microbial; microbiota; microbiota profiles; mortality; mouse model; next generation; oncolytic adenovirus; oncolytic virotherapy; pre-clinical; preclinical study; programs; standard care; synergism; tool; tumor; tumor progression; tumor-selective adenovirus

PILOT PROJECT 1: COMBINATION OF VIROIMMUNOTHERAPY AND MICROBIOTA MODULATION TO TREAT GASTRIC CANCER PROJECT SUMMARY/ABSTRACT Gastric cancer is the third leading cause of cancer-related mortality, with a 5-year survival rate of approximately 20%. The incidence and mortality rates of gastric cancer in the U.S. are of high concern, especially among non-white populations. Hispanic, black non-Hispanic, and Asian/Pacific Islander populations have a 40-50% higher risk of gastric cancer than white people, and African Americans are nearly twice as likely to die of stomach cancer. Virotherapy, as a special case of immunotherapy, is showing promising results for solid tumors in clinical trials. We developed an oncolytic adenovirus, Delta-24-RGD, which was clinically tested in a first-in-human phase I clinical trial in patients with recurrent glioblastoma. Clinical trials and preclinical studies showed that the intratumoral injection of Delta-24-RGD triggered an anti-tumor immune response that induced complete tumor regression in a small but significant percentage of patients. These clinical data emphasize the need to develop strategies that will significantly increase the percentage of solid tumors like gastric cancer sensitive to virotherapy. Recent studies showed that the intestinal microbiota influence the efficacy of immunotherapy. These clinical data have been supported by rigorously controlled experiments using gnotobiotic mouse models colonized with one or more specific bacteria, which showed that certain microbial biomarkers were associated with modulating and enhancing anti-tumor therapies, such as improving efficacy of immunotherapy. These data suggest that therapeutic interventions aimed at altering the gut microbiome may influence the final clinical outcome. Here, we hypothesize that oncolytic adenoviruses will exert an effective anti-cancer effect in gastric cancer, and that the host gut microbiome plays an important role in modulating the virus-driven anti-tumor response. To test this hypothesis, we propose the following aims: Aim 1. Characterize the anticancer-potency elicited by armed oncolytic adenovirus in gastric cancer. We will utilize the Delta-24-RGD platform of replication-competent, tumor-selective adenoviruses, and the next generation of Delta-24-RGD armed with the immunomodulator OX40L, Delta-24-RGDOX. Aim 2. Examine the role of gut microbial communities in modulating the efficacy of the viroimmunotherapy. We will assess the anti- cancer effect of the oncolytic therapy in relation to different bacterial signatures. This project should yield new information about the potential use of oncolytic adenoviruses as therapy for gastric cancer and will open avenues to include intestinal microbiota as a potential treatment modifier, by maximizing the synergy between laboratories at the University of Puerto Rico (UPR) and M.D. Anderson Cancer Center (MDACC). Our pilot project is aligned with the Infection-Driven Malignancies Program for Advancing Careers and Translational Sciences (IMPACT), in that it will allow us to generate preliminary data with potential to be translated into a full project to address a public health problem among the Hispanic population.

试点项目 1：病毒免疫疗法和微生物群调节相结合 治疗胃癌 项目概要/摘要 胃癌是癌症相关死亡的第三大原因，其 5 年生存率为 大约20%。美国胃癌的发病率和死亡率备受关注， 尤其是在非白人群体中。西班牙裔、非西班牙裔黑人和亚洲/太平洋岛民人口 患胃癌的风险比白人高 40-50%，非裔美国人的风险几乎是白人的两倍 死于胃癌。病毒疗法作为免疫疗法的一个特例，正在显示出有希望的结果 临床试验中的实体瘤。我们开发了溶瘤腺病毒Delta-24-RGD，并进行了临床测试 在复发性胶质母细胞瘤患者中进行的首次人体 I 期临床试验。临床试验和临床前 研究表明，瘤内注射 Delta-24-RGD 引发抗肿瘤免疫反应， 在一小部分但显着比例的患者中诱导肿瘤完全消退。这些临床数据 强调需要制定能够显着增加实体瘤比例的策略，例如 胃癌对病毒疗法敏感。最近的研究表明，肠道微生物群影响 免疫治疗的疗效。这些临床数据得到了严格控制的实验的支持 使用定植有一种或多种特定细菌的无菌小鼠模型，这表明某些细菌 微生物生物标志物与调节和增强抗肿瘤治疗相关，例如改善 免疫治疗的疗效。这些数据表明，旨在改变肠道的治疗干预措施 微生物组可能会影响最终的临床结果。在这里，我们假设溶瘤腺病毒将 对胃癌发挥有效的抗癌作用，宿主肠道微生物组发挥重要作用 调节病毒驱动的抗肿瘤反应。为了检验这一假设，我们提出以下目标： 目标 1. 表征武装溶瘤腺病毒在胃癌中引发的抗癌效力。我们将 利用具有复制能力、肿瘤选择性腺病毒的 Delta-24-RGD 平台，以及下一个 配备免疫调节剂 OX40L、Delta-24-RGDOX 的新一代 Delta-24-RGD。目标 2. 检查 肠道微生物群落在调节病毒免疫疗法疗效中的作用。我们将评估反 溶瘤疗法的癌症效应与不同细菌特征的关系。这个项目应该会产生新的 有关溶瘤腺病毒作为胃癌治疗的潜在用途的信息，并将开放 通过最大限度地发挥肠道微生物群之间的协同作用，将肠道微生物群作为潜在的治疗调节剂 波多黎各大学 (UPR) 和 MD 安德森癌症中心 (MDACC) 的实验室。我们的飞行员 该项目与感染驱动的恶性肿瘤职业发展计划保持一致， 转化科学（IMPACT），因为它将使我们能够生成有潜力的初步数据 转化为一个解决西班牙裔人口公共卫生问题的完整项目。