Targeting pancreatic cancer with adenoviral vectors equipped with transgenes

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, and current therapeutics provide limited benefits to patients. Desmoplasia and the highly immunosuppressive tumor microenvironment (TME) play a huge role in PDAC being elusive to current therapeutics. Here, we strategically selected four transgenes to express from adenovirus vectors to target desmoplasia and the highly immunosuppressive TME in PDAC: interferon gamma (IFNγ), extracellular domain of transforming growth factor beta receptor 2 (sTGFβRII), interleukin 7 (IL7), and the extracellular domain of T-cell Immunoglobulin and Mucin domain-containing protein 3 (sTIM3). We used an immunocompetent syngeneic mouse model harboring tumors derived from KPC cells, a common mouse pancreatic cancer cell line, to test the anti-tumor effects of our transgene-expressing Ad vectors. We showed that all four transgenes elicited significant anti-tumor effects and shifted the tumors to a more immunogenic profile by increasing intratumoral expression of immune activation proteins and infiltration of anti-tumor immune cells. Furthermore, inhibition of desmoplasia was observed in three of four proteins. Of the four transgenes analyzed, IFNγ and sTGFβRII induced the greatest anti-tumor results and were combined in a single Ad vector. This dual-expressing Ad vector elicited the greatest anti-tumor effect, increase in immunogenicity, decrease in fibrosis, and showed abscopal effects. These results provide insight into how the analyzed transgenes can favorably alter the TME in pancreatic cancer patients and show encouraging potential when combined with other therapeutic regimens.