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

试点项目1：病毒免疫治疗和微生物群调节相结合， 治疗胃癌 项目总结/摘要 胃癌是癌症相关死亡的第三大原因，5年生存率为 大约20%。在美国，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 患胃癌的风险比白色人高40-50%，非洲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种特殊情况， 临床试验中的实体瘤我们开发了一种溶瘤腺病毒Delta-24-RGD， 在复发性胶质母细胞瘤患者的首次人体I期临床试验中。临床试验和临床前期 研究表明，肿瘤内注射Delta-24-RGD引发抗肿瘤免疫应答， 在小但显著百分比的患者中诱导完全肿瘤消退。这些临床数据 强调需要制定策略，显着增加实体瘤的百分比， 胃癌对病毒治疗敏感。最近的研究表明，肠道微生物群会影响 免疫治疗的功效。这些临床数据得到了严格控制的实验的支持 使用一种或多种特定细菌定殖的无菌小鼠模型，这表明某些 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 免疫治疗的功效。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 在胃癌中发挥有效的抗癌作用，宿主肠道微生物组在其中起着重要作用， 调节病毒驱动的抗肿瘤反应。为了验证这一假设，我们提出了以下目标： 目标1.武装溶瘤腺病毒诱导胃癌细胞的抗肿瘤作用。我们将 利用Delta-24-RGD平台的复制能力，肿瘤选择性腺病毒，和下一个 用免疫调节剂OX 40 L，Delta-24-RGDOX武装的Delta-24-RGD的产生。目标二。检查 肠道微生物群落在调节病毒免疫疗法功效中的作用。我们将评估反- 溶瘤疗法的癌症效应与不同细菌特征相关。该项目将产生新的 关于溶瘤腺病毒作为胃癌治疗的潜在用途的信息， 包括肠道微生物群作为潜在的治疗调节剂的途径， 实验室在波多黎各大学（UPR）和M.D.安德森癌症中心（MDACC）。我们的飞行员 该项目与职业发展驱动的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初步数据， 转化为一个完整的项目，以解决西班牙裔人口的公共卫生问题。

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.