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: 10020950
• 负责人: Candelaria Gomez-Manzano
• 金额: $ 6.91万
• 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/10020950
• 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; Lesion; 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 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; 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：结合病毒免疫治疗和微生物群调节