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Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy
Cancer Cell  (IF31.743),  Pub Date : 2021-08-19, DOI: 10.1016/j.ccell.2021.07.023
Yujue Wang, Sixue Liu, Zhentao Yang, Alain P. Algazi, Shirley H. Lomeli, Yan Wang, Megan Othus, Aayoung Hong, Xiaoyan Wang, Chris E. Randolph, Alexis M. Jones, Marcus W. Bosenberg, Stephanie D. Byrum, Alan J. Tackett, Henry Lopez, Clayton Yates, David B. Solit, Antoni Ribas, Roger S. Lo

Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.