Preclinical monotherapeutic and anti-PD-1 synergistic anti-tumor efficacy of MNC-168, a novel human-derived live biotherapeutic product.

Abstract

e14581 Background: Human gut microbiome has been extensively demonstrated as a critical causative factor in determining the efficacy of cancer immunotherapy. Cumulative clinical evidences indicate the prevalent presence of Enterococcus species in the responder of anti-PD-1 treated patients. We here demonstrated the preclinical anti-tumor efficacy of a novel human derived Enterococcus strain MNC-168. Methods: Using multiple murine syngeneic cold tumor models and in vivo pharmacokinetics mouse model, we characterized the anti-tumor activity and pharmacokinetics of MNC-168 via oral-delivered route in monotherapy and immune checkpoint inhibitor (ICI) anti-mPD-1 combination. Systematic multi-omics analyses and in vitro mechanistic study were conducted to reveal the biomarkers and mode of action of MNC-168. Results: We found MNC-168 significantly and mono-therapeutically counteract tumor development in diverse tumor models, including colorectal cancer (with tumor inhibition ratio of 65.5%), hepatocellular carcinoma (27.4%), fibrosarcoma (33.5%) and renal carcinoma (56.4%). Notably, MNC-168 in combination with anti-mPD-1 synergistically exerted the tumor inhibition ratio up to 68.3-89.2% and significantly reverse anti-mPD-1 non-responsiveness. Integrated multi-omics analyses and in vitro validation study revealed the mechanism by which MNC-168 reinvigorates the immune system through targeting multiple routes, including activating systemic and tumor-resident innate and adaptive immunity, removal of tumor physical barrier, reinforced recruitment of tumor-infiltrating lymphocytes, and maintenance of immuno-stimulant activity via production of immune-simulating metabolites. Activation and boosting of interferon-γ production of CD8 T cells and CD4 T cells are the vital mediators for the anti-tumor ability of MNC-168. In vivo pharmacokinetics study shows that the anti-tumor efficacy of MNC-168 is positively correlated with gut-restricted abundance of MNC-168. Conclusions: MNC-168 is highly potently used as a first-in-class live biotherapeutic product for cancer monotherapy and promoting efficacy of ICI-mediated cancer immunotherapy.