Abstract 923: Pulsatile MEK inhibition improves anti-tumor immunity and T cell function in Kras mutant lung cancer

KRAS is one of the most commonly identified driver oncogenes in non-small cell lung cancer (NSCLC) and is frequently associated with disease refractory to currently available modalities of treatment. Targeted therapy to inhibit MEK signaling has shown promising tumor growth control in preclinical models, but is followed by quick rebound in tumor growth. Recently, immune checkpoint blockade has demonstrated clinical activity by dis-inhibiting T cells suppressed in the tumor microenvironment. Thus, we sought to identify the most effective therapy for the treatment of KRAS mutant NSCLC patients by targeting cancer cells and activating immune infiltrating cell populations concurrently. To achieve this, we focused on studying the impact of pulsatile MEK inhibition on the immune microenvironment utilizing Kras mutant lung cancer cell lines and Kras mutant transgenic lung cancer mouse models. We found that pulsatile MEK inhibition maintained T cell activation better than continuous treatment ex vivo and in vivo. Treatment with two different MEK inhibitors (selumetinib and trametinib) each resulted in higher CTLA-4 and PD-1 expression in T cells using pulsatile treatment, compared to continuous treatment ex vivo. In addition, the pulsatile schedule showed superior anti-tumor effects and delayed drug resistance compared to continuous administration in vivo. Further, a combination of pulsatile MEK inhibitor treatment and CTLA-4 blockade resulted in the most prolonged survival of Kras tumor-bearing mice. Similar experiments in immune-deficient mice confirmed that this prolonged survival is conferred by adaptive immunity. Our findings set the foundation for a combinatorial therapeutic strategy using pulsatile targeted therapy together with immune checkpoint blockade in patients to optimally enhance tumor apoptosis and promote long-term immune response simultaneously. We are now continuing our studies using a KRAS G12C inhibitor to define its immune modulating properties and will then rationally combine with immune based therapy. Citation Format: Hyejin Choi, Jiehui Deng, Shuai Li, Tarik Silk, Lauren Dong, Elliott J. Brea, Sean Houghton, David Redmond, Hong Zhong, Jonathan Boiarsky, Esra A. Akbay, Paul D. Smith, Taha Merghoub, Kwok-Kin Wong, Jedd D. Wolchok. Pulsatile MEK inhibition improves anti-tumor immunity and T cell function in Kras mutant lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 923.