Engineered Bifidobacterium secreting Super-mutant IL-2 significantly suppressed pancreatic cancer growth in mice

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, largely due to its inherent resistance to conventional therapies and a profoundly immunosuppressive tumor microenvironment (TME). This TME actively impairs the function of effector T (Teff) cells, critical for anti-tumor immunity. While Interleukin-2 (IL-2) is a potent T cell activator, its clinical utility is hampered by a short systemic half-life, dose-limiting systemic toxicity, and undesirable activation of regulatory T (Treg) cells, which further suppress immune responses. A targeted, TME-specific delivery of an improved IL-2 variant could overcome these limitations.

Researchers engineered Bifidobacterium longum, an obligate anaerobe known to selectively colonize the TME, to continuously secrete Super-mutant IL-2 (SumIL-2), an IL-2 variant designed to preferentially activate Teff cells over Treg cells. This novel probiotic, termed BifidoSumIL-2, was administered systemically to mice bearing both subcutaneous and orthotopic PDAC tumors. The primary endpoint was tumor growth suppression, alongside analysis of the Teff/Treg ratio within the TME. The study also investigated the therapeutic potential of BifidoSumIL-2 in combination with standard chemotherapy, radiation, and immunotherapy regimens against orthotopic PDAC.

Systemic administration of BifidoSumIL-2 significantly suppressed tumor growth in both subcutaneous and orthotopic PDAC mouse models. This therapeutic effect was accompanied by an improved Teff/Treg ratio, indicating a favorable shift in the immune landscape within the TME towards anti-tumor activity. The engineered SumIL-2, delivered locally by Bifidobacterium, successfully circumvented the systemic toxicity and off-target Treg activation typically associated with conventional IL-2 therapy. This localized delivery mechanism ensures that the potent immune-stimulating effects are concentrated where they are most needed, minimizing systemic exposure and maximizing local therapeutic concentrations.

Combining BifidoSumIL-2 with existing cancer treatments, including chemotherapy, radiation, and immunotherapy, further restrained orthotopic PDAC growth, demonstrating synergistic potential.

This suggests that localized, sustained delivery of a Teff-preferring IL-2 variant can overcome key barriers to effective immunotherapy in highly immunosuppressive cancers like PDAC. The probiotic's ability to selectively colonize the tumor site ensures targeted drug release, minimizing systemic exposure and maximizing local therapeutic concentrations.