Abstract 270: Preclinical assessment of combination therapy with selumetinib and CTLA-4 for cancer

Abstract

Abstract Immune mediated therapies for Cancer (IMT-C), such as anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies (mAb), are showing promise in the treatment of solid tumors. However, although these treatments demonstrate clinical activity in a range of tumors, the durable benefit of these agents appears to be limited to a subset of patients. One hypothesis is that activity in these patients is limited by a lack of immune priming or by additional immunosuppressive pathways. Combination with molecular targeted therapies offers the potential to explore additional treatment strategies for patients. However, in order to select the best combination partners, a greater understanding is needed as to how each therapy affects the immune system both directly, through effects on leukocytes, and indirectly, through effects on tumor immunogenicity and the microenvironment. Selumetinib is a potent inhibitor of the mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2), involved in the activation of signaling pathways which regulates cellular growth, proliferation and survival. Given that these pathways are often found aberrantly activated in human tumors, and also play key roles in the regulation of immunological processes, it is difficult to predict the combinatorial effect of MEK1/2 inhibition and IMT in cancer treatment. To assess the effect of selumetinib in a tumor model with an intact immune system, we have characterized the impact of dosing selumetinib with or without anti-CTLA-4 mAb on the immune system in the CT26 syngeneic tumor model. Flow cytometric analysis showed that this combination reduced T-cell proliferation and memory T-cell generation, but increased the frequency of splenic T cells. Selumetinib treatment decreased PD-L1 expression and increased MHC class II expression on the tumor cells, whilst decreasing myeloid-derived suppressor cell (MDSC)-like cells in the tumor. Despite the apparent ability of selumetinib to have both positive and negative effects on immune responses in vivo, the combination of selumetinib and anti-CTLA4 mAb was found to show anti-tumor activity in the CT26 colorectal tumor mouse model. These studies highlight the potential for enhancing anti-tumor immune response through combinations of molecular targeted therapies and IMT-Cs. Citation Format: Stefanie R. Mullins, Edmund Poon, Amanda Watkins, Paul D. Smith, Andrew Leishman, Ross Stewart, Robert Wilkinson. Preclinical assessment of combination therapy with selumetinib and CTLA-4 for cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 270. doi:10.1158/1538-7445.AM2015-270