Interferon-alpha enhances antitumor effect of chemotherapy in an orthotopic mouse model for pancreatic adenocarcinoma.

Data from a phase 2 trial combining chemoradiotherapy with interferon (IFN)-alpha (CapRI scheme) for adjuvant treatment of pancreatic carcinoma are very encouraging. Here, we try to evaluate the effect of IFN-alpha in this combined treatment scheme. Mice were inoculated with syngeneic cells in the pancreas. After 5 days animals were treated with 5-fluorouracil (5-FU), cisplatin (CDDP), radiation, and IFN-alpha. Tumor growth and immune responses were determined and adoptive cell transfer experiments performed. The impact of IFN-alpha treatment on leukocyte-endothelium interactions was assessed by intravital microscopy. Addition of IFN-alpha to chemotherapy had a significant life-prolonging effect. Regimens including IFN-alpha showed a clear trend toward less metastases than monotherapy. T cells and dendritic cells infiltrated tumors significantly more in 5-FU+IFN-alpha animals and these T cells secreted IFN-gamma tumor specifically. Antitumor response could be transferred by injection of mononuclear cells from 5-FU+IFN-alpha-treated mice into treatment-naive animals. The transferred cells homed to the tumors and proliferated there. Furthermore, significant more leukocytes were rolling and sticking to the endothelium. IFN-alpha significantly improves chemotherapy. This is mainly mediated by immunomodulation with improved adherence of leukocytes to the endothelium, infiltration, and lysis. Although IFN-alpha acts unspecifically an additional specific immune response could be demonstrated.