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Modulation of the gut microbiome to enhance efficacy of immunotherapy in pancreatic adenocarcinoma

调节肠道微生物组以增强胰腺腺癌免疫治疗的疗效

基本信息

批准号：
10010686
负责人：
Xin Li
金额：
$ 39.98万
依托单位：
PERIOMICS CARE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10010686
关键词：
Ablation Animal Model Animals Anti-Inflammatory Agents Antibiotic Therapy Antibiotics Antineoplastic Agents Automobile Driving Bacteria CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cancer Etiology Cancerous Caring Cellulose Centers for Disease Control and Prevention (U.S.)Cessation of life Clinic Clinical Clinical Trials Design Collaborations Data Development Disease Disease Progression Equilibrium Formulation Freeze Drying Health Health Expenditures Homeostasis Human Immune Immunooncology Immunosuppression Immunotherapy Incidence Inflammatory Innate Immune Response Intervention Malignant Neoplasms Malignant neoplasm of pancreas Medical Care Costs Molecular Monitor Mus Myeloid Cells Myeloid-derived suppressor cells Myeloproliferative disease Non-Small-Cell Lung Carcinoma Oncogenic Oral Pancreas Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Patients Pharmacologic Substance Phase Phenotype Play Population Probiotics Protocols documentation Regimen Regulatory T-Lymphocyte Reporting Research Resistance Role Signal Transduction Small Business Technology Transfer Research Survival Rate T-Cell Activation T-Lymphocyte Testing Therapeutic United States United States Agency for Healthcare Research and Quality Woman Work anti-PD-1 antimicrobial antitumor effect base cancer risk cancer therapy commensal bacteria cytokine gut microbiome immune activation immune checkpoint blockade immunogenic improved innovation macrophage medical schools melanoma men microbiome novel therapeutics pathogenic bacteria phase 1 study probiotic therapy programmed cell death protein 1 programs recruit success therapeutic target tumor tumor microenvironment tumor progression tumorigenesis tumorigenic

项目摘要

Abstract Pancreatic ductal adenocarcinoma (PDA) is among the ten most common cancers for both men and women. According to CDC the incidence rates of pancreatic cancer have been rising by almost 1.2% each year over the last 10 years. The 5-year survival rate is less than 7%. Despite the recent success of checkpoint blockade- based monotherapy in human melanoma and non-small cell lung cancer, many PDA patients do not experience durable clinical benefit. We postulated that in addition to oncogenic signals and anti-inflammatory cytokines, the microbiome plays an important role in instructing the pro-tumoral innate immune response. We found that PDA is associated with a distinct stage specific gut/pancreatic microbiome and it drives disease progression by inducing intratumoral immune suppression. In this STTR Phase 1 proposal we will determine a role for probiotic administration to restore the species that are associated with decreased cancer risk. Based on our previous work on microbiome and PDA we have made a cocktail of 8 bacterial strains (POC518) which help to maintain gut homeostasis. In Aim 1 we will develop a cellulose based formulation of probiotics cocktail POC518. Further in In Aim 2, we will directly assess the efficacy of POC518 formulation in improving αPD-1’s anti-tumor effects using two PDA animal models. We will monitor tumor progression and animal survival, molecular oncogenesis, and peri-tumoral immune activation in the PDA animal models receiving αPD-1 monotherapy or combined therapies with antibiotics and/or probiotics. At the completion of listed milestone, we will have a developed and assessed a probiotics formulation using microbiome directed intervention strategies to improve checkpoint-based immunotherapy. Findings from this Phase I study will enable us to design clinical trials in collaboration with other pharmaceuticals companies. We strongly believe that modulation of the gut microbiome will have dramatic implications in the immunotherapies for pancreatic cancer treatment.

摘要