Anti-PD-L1 Lead-in Before MAPKi Combination Maximizes Anti-Tumor Efficacy and Immunity [TCRseq]

Indications of PD-1/L1- and MAPK-targeted therapies cross cancer histologies. Rationally sequencing and/or combining them may overcome innate and acquired resistance. We observed increased clinical benefit of BRAF andV600MUT/MEK inhibitors in patients with advanced BRAFV600MUT melanoma who were previously treated with immune checkpoint therapy (ICT). To test whether ICT primes MAPK inhibitor (MAPKi) efficacy, we compared sequential/combinatorial regimens in subcutaneous mouse tumors driven by BrafV600, Nras, Nf1 or Kras mutations. The most efficacious regimen consisted of anti-PD-L1 lead-in preceding MAPKi combination and specifically promoted intratumoral pro-inflammatory macrophages and clonal expansion of IFNhi, CD8+ cytotoxic T-cells (relative to CD4+ regulatory T-cells) that highly expressed activation and cytolytic genes. Since melanoma brain metastasis (MBM) and its propensity for therapeutic resistance limit patient survival, we developed an experimental metastasis model of BrafV600MUT MBM. Sequencing anti-PD-L1 before MAPKi combination resulted in superior MBM control and survival as well as robust intratumoral T-cell clonal expansion both intracranially and extracranially. We propose that brief anti-PD-1/L1 dosing prior to MAPKi co-treatment suppresses resistance. This dataset contains the TCR-seq of brian and ovary metastases in murine melanoma model (Braf mutated) under different treatment conditions