Therapy with fecal microbiota transplantation and immune checkpoint blockade for solid tumors

粪便微生物群移植和免疫检查点阻断治疗实体瘤

• 批准号: 10650717
• 负责人: GIORGIO TRINCHIERI
• 金额: $ 42.77万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-16 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650717
• 关键词: Address; Age; Antitumor Response; Applications Grants; Bioinformatics; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Clinical; Clinical Trials; Computer Analysis; Correlative Study; Diet; Engraftment; Exhibits; Funding; Funding Agency; Gene Expression Profile; Geographic Locations; Human; Human Papillomavirus; Immune; Immunologics; Immunosuppression; Innate Immune Response; Intake; Lymphocyte; Malignant Neoplasms; Monoclonal Antibodies; Multiomic Data; Mus; Mutation; Myelogenous; Non-Small-Cell Lung Carcinoma; Organism; Outcome; Pathway Analysis; Patients; Performance; Pharmaceutical Preparations; Phase II Clinical Trials; Progression-Free Survivals; Refractory; Reporting; Research Proposals; Resistance; Role; Serious Adverse Event; Serum; Site; Solid Neoplasm; T-Cell Activation; T-cell inflamed; Translational Research; Translations; United States National Institutes of Health; Universities; Virus; adaptive immune response; anti-CTLA4; anti-PD-1/PD-L1; anti-PD1 antibodies; cancer immunotherapy; cancer infiltrating T cells; clinical center; cohort; fecal transplantation; first-in-human; gut microbiome; gut microbiota; immune checkpoint blockade; immune-related adverse events; improved; melanoma; metabolomics; microbial; microbiome; microbiome composition; microbiota; neutrophil; novel; novel therapeutics; phase 2 study; predict clinical outcome; predictive marker; programmed cell death ligand 1; programmed cell death protein 1; refractory cancer; resistance mechanism; response; response biomarker; sex; systemic inflammatory response; tumor; tumor microenvironment

ABSTRACT Immune checkpoint blockade (ICB) with blocking anti-CTLA-4 and/or anti-PD-1/PD-L1 monoclonal antibodies (mAbs) have induced durable clinical responses in patients with solid tumors, including melanoma, non-small cell lung cancer (NSCLC), and HPV+ cancers. However, the majority of cancer patients still fail to respond to ICB, supporting the need to identify predictive biomarkers of response, and develop novel therapies to overcome the mechanisms of resistance to ICB. Multiple studies have reported that a human beneficial gut microbiome is associated with response to anti-CTLA-4 or anti-PD-1 mAbs in cancer patients. Strikingly, there is limited concordance among species identified across different studies, which included small number of patients and used different analytical approaches. In addition, the administration of certain gut commensals or responder-derived fecal microbiota transplantation (FMT) promotes efficacy of anti-CTLA-4 and anti-PD1 mAbs in melanoma-bearing mice. Reintroduction of beneficial organisms and/or fecal microbiota transplantation (FMT) from responding mice restores sensitivity to ICB in tumor-bearing mice. Responder-derived FMT resensitized melanoma patients to anti-PD1 mAbs in two separate studies. In a first-in-human phase II study, we reported that R-FMT provided clinical benefit primary refractory melanoma patients, induced rapid and durable microbiota perturbation. Bioinformatic analysis demonstrated that the FMT-induced changes of the gut microbiome in treated patients governed the observed immunological and metabolomic changes in the periphery and at tumor sites. Our novel preliminary findings in melanoma support that baseline beneficial and detrimental enterotypes predict clinical outcome and immune-related adverse events (irAEs) in PD1-treated melanoma. They also support the hypotheses that FMT exhibiting a beneficial enterotype may :1) improve clinical outcome upon ICB, and 2) impede the occurrence of serious irAEs. Whether these findings in patients with advanced melanoma are relevant to large cohorts of cancer patients with melanoma, NSCLC or HPV+ cancer in distinct geographic locations has not been determined yet. These important questions are addressed in the present translational research proposal. This collaborative project in response to PAR 18-951 between the University of Pittsburgh and the NCI will take advantage of the NIH Clinical Center's unique access to a large cohort of patients with HPV+ cancers treated with cancer immunotherapy.

摘要