Abstract 2334: Anti-cancer efficacy of the combination with immunomodulatory antibodies and MEK inhibitor for Kras mutation and p53 knockout driven lung cancer
Authors: Lee Jong Woo , Zhang Yu , Park Hee Sun , Park Sin Aye , Koo JaSeok Peter , Herbst Roy S. 
Published: July 2016

Lung cancer remains a major cause of cancer mortality. Malignant lesions are normally endogenously corrected by the immune surveillance system. However, tumors evade this immunity by inducing immunosuppressive microenvironments during cancer progression. It has been thought that there are two critical components of tumors making them capable of maintaining the immunosuppressive microenvironment. One is the inhibition of cytotoxic T lymphocytes (CTL) activity against the tumor through immune checkpoint molecules, such as programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1), which are negative regulators of CTL, and the other is by the induction of tumor infiltrating immune suppressive cells, which can deactivate the CTL. Recent studies demonstrate that multiple cancer types, including melanoma, lung, kidney, bladder, and stomach, respond to immune checkpoint inhibitors, such as PD-L1 and PD-1 with 11-30% response rates and durable responses. However, a substantial number of patients still fail to respond to immunotherapy and the refractory mechanisms are largely unknown. In this study, we focus on KRas-driven lung cancers, as there are no clinically effective targeted drugs available for treating this type of lung cancer. We demonstrate that during the progression of tumors in KRas mutation and p53 knockout-driven lung cancer mouse models; KRasG12D/+;p53-/- (KP), there is a gradual increase in the number of myeloid derived suppressor cells (MDSC) and that the combination of either anti-PD-1 or anti-PD-L1 antibody along with a MEK inhibitor, which targets downstream of KRas signaling, shows anticancer efficacy in these animal models. These combinations, in comparison to either single agent alone, effectively blocks the growth of subcutaneously (s.c.) injected syngeneic mouse lung cancer cells in immune competent transgenic KP mice, significantly increasing the survival rates: 37.5% (for anti-PD-1 antibody and MEK inhibitor), 62.5% (for anti-PD-L1 antibody and MEK inhibitor) vs. 0% single agents or control at the end of treatment. We find that the tumors in the control treated group harbor a substantial number of immune cells, including PD-L1 expressing MDSC. The combination treatment with either an anti-PD-1 or anti-PD-L1 antibody along with a MEK inhibitor dramatically modulates the composition and the activity of tumor infiltrated immune cells. Tumors in the combined treated group show a significant decrease in PD-L1 expressing MDSC in comparison with control tumors. Additionally, a combined treatment would block the PD-L1 activity of the infiltrated PD-L1 expressing MDSC in malignant tumors and thus lead to improved survival. These results point to a potential therapeutic opportunity for currently untargetable KRas-driven lung cancers.

Citation Format: Jong Woo Lee, Yu Zhang, Hee Sun Park, Sin Aye Park, JaSeok Peter Koo, Roy S. Herbst. Anti-cancer efficacy of the combination with immunomodulatory antibodies and MEK inhibitor for Kras mutation and p53 knockout driven lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2334.