Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

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. [Display omitted] •Prior ICT is associated with longer PFS of melanoma patients treated with MAPKi•Anti-PD-1/L1 before MAPKi combination prolongs durability of tumor regression•Targeting M2-TAMs augments and CD8+ T cells abolishes priming-associated benefit•Anti-PD1/L1 plus anti-CTLA-4 priming may further control melanoma brain metastasis Wang et al. couple in vivo preclinical therapeutic testing with temporal single-immune cell and T cell clonotype analysis to identify a sequential-combinatorial regimen and cellular effectors associated with the most durable control of tumor growth and brain metastasis. Initiating immune checkpoint therapy briefly before adding MAPK-targeted therapy may improve patient survival.