Abstract 2712: Effect of combined PD-1 and IL-6 blockade on K-ras mutant lung cancer

Abstract

Abstract Lung cancer is the leading cause of cancer death and the second most common cancer diagnosed worldwide in both males and females. K-ras gene mutations are among the most common mutations encountered in non-small cell lung cancer (NSCLC), encompassing up to 30% of them, and are unfortunately associated with chemoresistance and poor prognosis. Recently, immunotherapy treatment of several cancers including NSCLC, particularly by targeting the co-inhibitory molecules program cell death protein 1 (PD-1) and program death-ligand 1 (PD-L1), have shown promising results given either in combination with standard chemotherapy or as neoadjuvant therapy. We have previously shown an important role for IL-6 in K-ras mutant lung tumorigenesis by reprogramming myeloid contexture in the lung tumor microenvironment (TME) and promoting tumor cell proliferation and angiogenesis through the activation of STAT3 pathway. Accordingly, we hypothesized that targeting both immunosuppressive TME and IL-6 driven pro-tumor immune response, through the use of immune checkpoint blockade (ICB), and inhibition of IL-6 would give us a synergistic/additive response and increases the tumor inhibitory effect of ICB. Briefly, starting at the age of 6 weeks, 4 cohorts of K-ras mutant mice (LSL-K-rasG12D/ CCSPCre) (CC-LR) were injected intraperitoneally with vehicle alone (PBS1x), anti-PD-1 (CD279) antibody alone (Clone: 29F.1A12- Bioxcell - BE0273-CUST) (200µg), anti-IL-6 antibody alone (Clone: MP5-20F3 - Bioxcell - BE0046-CUST) (20 mg/kg), or a combination of both. After 8 weeks of treatment, tumor burden and inflammation were studied and quantified. We found a significant (2-fold) decrease in tumor burden in the anti-PD1 alone treated group which was further reduced in the combined anti-PD-1 and anti-IL-6 treated group compared to age and sex matched vehicle treated group. There was also a significant difference in the lung macrophage infiltration in combined anti-PD1/anti-IL-6 treated group similar to what we previously observed in anti-IL-6 alone treated group. Our results suggest that immunomodulatory approaches by targeting cytokine networks like IL-6 blockade could be used to increase the efficacy of immunotherapy, i.e. PD-1 blockade, as a preventive and/or therapeutic strategy for K-ras mutant lung cancer. Citation Format: Marco A. Ramos-Castaneda, Neha Daga, Stephen Peng, Shanshan Deng, Walter Velazco, Mauricio Da Silva Caetano, Seyed Moghaddam. Effect of combined PD-1 and IL-6 blockade on K-ras mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2712.