Combined innate immune cell therapy, tumor-specific antibody, and radiation prompt antitumor response in pancreatic cancer models

Pancreatic ductal adenocarcinoma (PDAC) is generally resistant to conventional immunotherapies due to its immunosuppressive tumor microenvironment (TME). We combine an innate cell-enriched product activated by interleukin-2 (IL-2) and zoledronic acid (ZA) (ICP^IL2ZA) with low-dose radiotherapy (RT) and monoclonal antibodies (mAbs) to overcome this immunosuppressive TME. ICP^IL2ZA is composed of natural killer (NK) cell- and monocyte-enriched immune cells, activated ex vivo with IL-2 and ZA. ICP^IL2ZA with RT and mAbs promotes antibody-dependent cellular cytotoxicity and phagocytosis against PDAC. In murine models of PDAC, RT and mAb combined with ICP^IL2ZA derived from either murine or healthy human donors controlled tumor growth. RT amplifies ICP^IL2ZA effectiveness by inducing NKG2D ligands on tumor cells, facilitating immune infiltration that leads to tumor growth control and extends survival without apparent toxicity. These results suggest that ICP^IL2ZA can overcome limitations of traditional therapies by augmenting antitumor capabilities of endogenous immune cells, highlighting a promising autologous strategy for PDAC and other immunologically "cold" tumors.