The University of Chicago has received a USD 1.75 million National Cancer Institute R01 award to develop genetically engineered Bifidobacterium as a systemic delivery vehicle for immunotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC), one of the cancers least responsive to existing treatments.
The award, funded under the NCI's "Bugs as Drugs" program (PAR-22-085), supports co-investigators Mark Mimee and Ralph Weichselbaum through June 2029. The project targets a disease where checkpoint immunotherapy and radiotherapy have demonstrated limited efficacy, partly due to an immunosuppressive tumor microenvironment (TME) dominated by tumor-associated macrophages and depleted of T cells.
The core strategy exploits Bifidobacterium longum, a human commensal anaerobe that preferentially colonizes hypoxic tumor regions following intravenous administration. The team has developed genetic tools to engineer the bacterium to secrete a modified interleukin-2 variant (SumIL2) directly within the TME, with a built-in gene circuit controlling both cytokine release and bacterial self-destruction. Preliminary data indicated that systemic Bifidobacterium administration converted non-responding mice into responders to anti-CD47 immunotherapy and radiotherapy, providing preclinical proof-of-concept for the combination approach.
The IL-2 delivery angle addresses a long-standing clinical problem: systemic IL-2 administration carries significant toxicity that has constrained its use in oncology. By restricting cytokine secretion to the tumor site through bacterial colonization, the approach aims to preserve efficacy while reducing off-target effects. The self-destruction circuit adds a further safety mechanism not present in earlier bacterial vector platforms.