Tumor-Selective Bacterial Therapy to Reverse PDAC Immunosuppression

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Pancreatic cancer (PanC) is among the most lethal malignancies, characterized by dense fibrotic stroma, a highly immunosuppressive tumor microenvironment (TME), and resistance to immunotherapies. Current treatment strategies, including chemotherapy, are limited by toxicity and eventual resistance, resulting in poor survival outcomes. To address these challenges, we propose iSTORM, an innovative microbial-based therapy that combines tumor-specific targeting, stromal remodeling, and immune reprogramming. iSTORM is a genetically engineered strain of Salmonella typh. that preferentially colonizes PanC tumors via recognition of mannose-rich glycans. It delivers inhibitory RNA against CMTM6, a key regulator of PD-L1 stability and other immune evasion mechanisms, to restore anti-tumor immunity while reducing stromal barriers to treatment. Preclinical data show that iSTORM robustly colonizes primary and metastatic pancreatic tumors, induces direct cancer cell killing, reprograms surviving tumor cells to express immune-recruiting chemokines and antigenpresentation molecules, and increases effector immune cell infiltration. However, we find that suppressive myeloid populations, myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), persist after treatment, limiting long-term efficacy. The central hypothesis is that iSTORM overcomes the main barriers to pancreatic cancer therapy by leveraging tumor-specific glycan targeting and immune reprogramming, but durable responses require co-targeting of persistent myeloid suppression. We will test this hypothesis through three aims: (1) Define the molecular basis of iSTORM’s tumor-selective colonization via cancer-specific N-glycans using genetic and pharmacological perturbation in syngeneic and genetically engineered mouse models. (2) Dissect how iSTORM reprograms tumor cells to drive immune conversion and identify suppressive myeloid populations as the major resistance node, using spatial multi-omics and immune subset depletion. (3) Establish the therapeutic efficacy of iSTORM monotherapy and in combination with myeloid-directed agents (gemcitabine, anti-Ly6G, and anti-CSF1R) in preclinical models, defining immune correlates of durable response and memory. This project will advance the mechanistic understanding of bacteria-based Immunotherapeutics like iSTORM, a novel intervention poised to overcome PanC’s unique therapeutic barriers, thereby driving a paradigm shift in cancer treatment and paving the way for first-in-human clinical trials. Animal models are necessary for this project because evaluating the complex interactions between the engineered bacteria, the dense tumor stroma, and the host's intact immune system requires a living, systemic physiological model that cannot be replicated in vitro.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic cancer is one of the deadliest cancers, with limited treatment options due to its dense fibrotic tissue and suppression of the immune system. We are developing iSTORM, a groundbreaking therapy using genetically engineered bacteria that specifically target tumors, remodel the tumor environment, and restore immune function. By combining direct tumor targeting with immune reprogramming, iSTORM offers a promising new strategy to overcome current therapeutic barriers and improve outcomes for patients.