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

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.Project Narrative Pancreatic ductal adenocarcinoma (PDA) is the third most lethal cancer in the United States and accounts for 85% of all pancreatic malignancies. The proposed studies will develop new microbiome based therapeutic approaches for treating PDA.