Novel combination therapy with imiquimod and sorafenib for renal cell carcinoma.

OBJECTIVES: To investigate whether the combination of the imidazoquinoline immune response modifier, imiquimod, and the multitargeted tyrosine-kinase inhibitor, sorafenib, inhibits the growth of renal cell carcinoma in mice. METHODS: Female BALB/c mice were implanted subcutaneously with 2 × 10(5) RENCA mouse kidney cancer cells, and were treated with transcutaneously applied cream containing imiquimod and oral administrations of sorafenib beginning 5 days after implantation of the cells. Tumor incidence and burden were determined at 28 days after initiation of therapy. T cell infiltration in the tumor was determined by immunofluorescence staining with anti-CD3-ε and CD8-α antibodies. RESULTS: Therapy with imiquimod, sorafenib or their combination was well tolerated. Combination therapy with imiquimod and sorafenib significantly inhibited tumor growth when compared with administration of control vehicle, imiquimod or sorafenib alone (P < 0.05). The CD3- and CD8-positive T cells infiltrated into tumors to a greater degree in response to the combination therapy when compared with tumors treated with control vehicle or sorafenib alone. CONCLUSIONS: Combination therapy with a tyrosine-kinase inhibitor and an imidazoquinoline could be a promising therapeutic strategy for patients with renal cell carcinoma.

Mice lacking the IFN-gamma receptor or fyn develop severe experimental autoimmune uveoretinitis characterized by different immune responses.

Endogenous interferon (IFN)-gamma negatively regulates experimental autoimmune uveoretinitis (EAU), a Th1-mediated disease. Although it is well known that IFN-gamma exerts its effects by binding to the IFN-gamma receptor (IFN-gammaR), the role that IFN-gammaR plays in the development of EAU has not been investigated. Fyn has been reported to inhibit Th2 differentiation. We aimed to investigate how endogenous IFN-gammaR and fyn, which influence Th1/Th2 differentiation, participate in the development of EAU. Sex-matched 6- to 10-week-old C57BL/6 wild-type (WT), IFN-gammaR knockout (GRKO) and fyn knockout (fyn KO) mice were compared. Mice were immunized subcutaneously with human interphotoreceptor retinoid-binding protein peptide 1-20 emulsified in Freund's complete adjuvant together with an intraperitoneal injection of Bordetella pertussis toxin. Three weeks later, mice were sacrificed, and their eyes and spleens were harvested for histopathologic analyses and examination of cellular immune responses, respectively. Cellular immune responses were evaluated by measuring the proliferative responses and cytokine production [interleukin (IL)-4, IL-5, IL-6, IL-13, IFN-gamma and tumor necrosis factor (TNF)-alpha] of splenocytes. The incidence of EAU was 40.0% in WT mice, 59.3% in GRKO mice and 78.6% in fyn KO mice. The average EAU score was 0.294 in WT mice, 0.917 in GRKO mice and 1.063 in fyn KO mice. Upon EAU induction, significant infiltration of eosinophils into the eyes was observed in GRKO and fyn KO mice compared to WT mice. Splenocytes from GRKO mice proliferated against the antigen and a mitogen more vigorously than those from WT and fyn KO mice. Stimulation of splenocytes with the antigen induced a higher production of IL-4, IL-6, IL-13 and IFN-gamma in GRKO mice compared to WT and fyn KO mice. In contrast, IL-5 and TNF-alpha were most abundantly produced by splenocytes from fyn KO mice compared to WT and GRKO mice. The incidence and mean severity of EAU were significantly higher in GRKO and fyn KO mice than in WT mice, suggesting that endogenous IFN-gammaR and fyn negatively regulate the development of EAU. The different cytokine production patterns by the GRKO and fyn KO mice indicate that the negative regulatory mechanism mediated by IFN-gammaR and fyn may differ.