Optimizing targeted therapy and immune checkpoint blockade therapy in Kras mutant lung cancer Hyejin Choi1*, Jiehui Deng3*, Shuai Li3*, Tarik Silk1, Eliot Brea1, Jonathan Boirasky1, Esra A Akbay4, Paul D. Smith5, Taha Merghoub2†, Kwok-Kin Wong3†, Jedd Wolchok2† 1Department of Immunology, 2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065; 3Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016; 4Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; Simmons Comprehensive Cancer Center, Dallas, Texas; 5AstraZeneca Ltd, Cambridge, UK *These authors contribute equally to this work †Co-corresponding authors KRAS is one of the most commonly identified driver oncogene in non-small cell lung cancer (NSCLC) and is commonly associated to NSCLC that are refractory to current available modalities of treatment. Targeted therapy to inhibit MEK has shown promising tumor growth control, but is followed by quick rebound of tumor growth. Recently, cancer immunotherapy has shown great promise by activating T cells that are suppressed in the tumor microenvironment, especially through targeting co-inhibitory molecules and their counterparts. We sought to identify the most effective therapy for the treatment of KRAS mutant NSCLC patients by targeting cancer cells and activating immune infiltrates at the same time, by studying the impact of MEK inhibition on the immune microenvironment. We find that pulsatile treatment of MEK inhibitors activates T cells and releases their proliferation suppression. Both selumetinib and trametinib showed highly increased CTLA-4 expression and mild increase of PD-1 in T cells in intermittent treatment, compared to continuous treatment in vivo. In addition, the intermittent schedule alone showed superior anti-tumor effect and delayed drug resistance, in contrast with continuous dosing schedule. Based on the above observations, we combined intermittent MEK inhibitor treatment and anti-CTLA-4 and found that it showed most prolonged survival of Kras tumor bearing mice. All together our findings will set the foundation for a combinatorial therapeutic strategy using intermittent targeted therapy together with immunotherapy in patients, to optimally enhance tumor apoptosis and promote long-term immune response simultaneously.
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