NIH grant: Tumor-Selective Bacterial Therapy to Reverse PDAC Immunosuppression (1R01CA314284-01)

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NIH grant 1R01CA314284-01: Tumor-Selective Bacterial Therapy to Reverse PDAC Immunosuppression
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Chiswili Yves Chabu. Award: $633763.
Start: 2026-08-15T00:00:00.
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.

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