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: 10249301
• 负责人: Candelaria Gomez-Manzano
• 金额: $ 6.42万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 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/10249301
• 关键词: Address; African American; Antigens; Antitumor Response; Asian Pacific Islander; 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; Lesion; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Mus; Not Hispanic or Latino; OX40; Oncolytic; Operative Surgical Procedures; Outcome; 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 therapy; anti-cancer; anti-tumor immune response; anticancer research; base; cancer initiation; career; clinical application; disparity reduction; effector T cell; experimental study; fecal transplantation; first-in-human; gastric organoids; gut microbiome; gut microbiota; high risk; immune checkpoint; immunological synapse; immunotherapeutic virotherapy; improved; in vivo; malignant stomach neoplasm; melanoma; member; microbial; microbiota; microbiota profiles; mortality; mouse model; next generation; oncolytic adenovirus; oncolytic virotherapy; pre-clinical; preclinical study; programs; sex; 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：将微生物免疫技术和微生物区系调制相结合 治疗胃癌 项目摘要/摘要 胃癌是癌症相关死亡的第三大原因，其5年存活率为 大约20%。美国的胃癌发病率和死亡率令人高度关注， 尤其是在非白人人群中。西班牙裔、非西班牙裔黑人和亚洲/太平洋岛民 患胃癌的风险比白人高40%-50%，而非裔美国人患胃癌的可能性几乎是白人的两倍 死于胃癌。病毒治疗作为免疫治疗的一种特例，在临床上显示出良好的治疗效果。 实体肿瘤正在进行临床试验。我们开发了一种溶瘤的腺病毒Delta-24-RGD，并进行了临床测试 在对复发性胶质母细胞瘤患者进行的首个人类I期临床试验中。临床试验和临床前研究 研究表明，瘤内注射Delta-24-RGD引发了抗肿瘤免疫反应， 在一小部分患者中诱导肿瘤完全消退，但比例很大。这些临床数据 强调需要制定战略，显著提高实体肿瘤的百分比，如 胃癌对病毒治疗敏感。最近的研究表明，肠道微生物区系影响着 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。 使用被一种或多种特定细菌定植的诺生菌小鼠模型，这表明某些 微生物生物标记物与调节和加强抗肿瘤治疗有关，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 微生物群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，而宿主肠道微生物群起着重要作用 在调节病毒驱动的抗肿瘤反应方面。为了验证这一假设，我们提出了以下目标： 目的1.研究武装溶瘤腺病毒在胃癌中的抗癌活性。我们会 利用Delta-24-RGD平台的复制能力强、对肿瘤具有选择性的腺病毒，以及Next 用免疫调节剂OX40L，Delta-24-RGDOX武装的Delta-24-RGD的产生。目标2.检查 肠道微生物群落在调节病毒免疫治疗疗效中的作用。我们将评估反- 肿瘤溶解治疗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 关于溶瘤腺病毒作为胃癌治疗的潜在用途的信息，将公开 将肠道微生物区系作为潜在的治疗改良剂的途径，通过最大限度地提高 波多黎各大学(UPR)和安德森癌症中心(MDACC)的实验室。我们的飞行员 该项目与感染驱动的恶性肿瘤计划保持一致，以促进职业生涯和 翻译科学(IMPACT)，因为它将使我们能够生成具有潜在潜力的初步数据 转化为一个完整的项目，以解决拉美裔人口中的公共卫生问题。