Abstract 5596: Enhanced anti-tumor effect of combination therapy with anti-CD40 antibody and the mTOR kinase inhibitor AZD8055

Abstract

Abstract mTOR signaling, which plays a central role in controlling cell cell proliferation, survival, mobility and angiogenesis, is considered an important target for new anticancer drugs development. The involvement of the CD40/CD154 signaling pathway has also been reported to play an important role in regulating anti-tumor immune responses. In this study, using a first-in-class orally bioavailable mTOR kinase inhibitor, AZD8055, which, unlike rapamycin, can inhibit both mTORC1 and mTORC2, we evaluated the anti-tumor efficacy of mTOR kinase inhibitor treatment alone in a murine model of metastatic renal cell carcinoma (Renca) and compared biological responses achieved by administering AZD8055 as a single agent to those obtained in combination with agonistic anti-CD40 antibody. In vitro survival assays showed that Renca cell apoptosis could be induced by AZD8055. In vivo, although both agents administered alone had some anti-tumor efficacy, the combination of AZD8055 and CD40 Ab induced a significant anti-tumor response in both intra-renal and intra-splenic inoculations model of renal cell carcinoma, as compared to single agent treatments. The combination treatment, also resulted in an increase and activation of tumor- and liver-associated macrophages, NK cells and CD8 T cells in vivo. AZD8055/anti-CD40 treatment also increased the level of systemic Th1 cytokines, including IL-12, IFN-γ, TNFα. IFN-γ production by CD8+ T cells and TNFα production by macrophages were also found to be elevated in the AZD8055/anti-CD40 combination treated-group, compared with any single treatment group. Furthermore, the expression of Th1-associated chemokines, RANTES and IP10, were significantly induced in the combination treated-group. These data suggest that the combination of mTOR kinase targeting agents with immunotherapy could be an area of further development in renal cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5596.