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: 10247768
• 负责人: FILIPA GODOY-VITORINO
• 金额: $ 0.94万
• 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/10247768
• 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制的组合 治疗胃癌 项目摘要/摘要 胃癌是癌症相关死亡率的第三主要原因，其存活率为5年 约20％。美国胃癌的发病率和死亡率令人关注， 特别是在非白人人群中。西班牙裔，黑人非西班牙裔和亚洲/太平洋岛民人口 胃癌风险高40-50％，而非洲裔美国人的可能性几乎是两倍 死于胃癌。作为免疫疗法的一种特殊情况，病毒疗法正在显示出令人鼓舞的结果 临床试验中的实体瘤。我们开发了溶瘤腺病毒Delta-24-RGD，该病毒经过临床测试 在人类的第一阶段临床试验中，对复发性胶质母细胞瘤患者。临床试验和临床前试验 研究表明，Delta-24-RGD的肿瘤内注射引发了抗肿瘤免疫反应， 在一小部分但很大一部分的患者中诱导了完全的肿瘤回归。这些临床数据 强调需要制定将大大增加实体瘤百分比之类的策略 对病毒疗法敏感的胃癌。最近的研究表明，肠道菌群影响 免疫疗法的功效。这些临床数据已通过严格控制的实验支持 使用用一种或多种特异性细菌殖民的gnotobiotic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疗法有关，例如改善 免疫疗法的功效。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将 在胃癌中发挥有效的抗癌作用，宿主肠道微生物组起重要作用 在调节病毒驱动的抗肿瘤反应时。为了检验这一假设，我们提出以下目的： AIM 1。特征是胃癌中武装的溶瘤腺病毒引起的抗癌剂量。我们将 利用复制能力，肿瘤选择性腺病毒的Delta-24-RGD平台和下一个 由免疫调节剂OX40L，Delta-24-RGDOX武装的Delta-24-RGD生成。目标2。检查 肠道微生物群落在调节病毒免疫疗法的功效中的作用。我们将评估抗 溶瘤疗法与不同细菌特征有关的癌症作用。这个项目应产生新的 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 通过最大化协同作用 波多黎各大学（UPR）和M.D. Anderson癌症中心（MDACC）的实验室。我们的飞行员 项目与以感染驱动的恶性肿瘤计划保持一致，以促进职业和 翻译科学（影响），因为它将使我们能够生成具有潜力的初步数据 转化为一个完整的项目，以解决西班牙裔人口中的公共卫生问题。