The ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis.

Abstract

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; however, only a subset of patients with brain metastasis (BM) respond to ICI. Activating mutations in the mitogen-activated protein kinase (MAPK) signaling pathway are frequent in BM. The objective of this study was to evaluate whether therapeutic ERK inhibition can improve the efficacy of ICI for BM. We used immunotypical mouse models of brain metastasis bearing dual extracranial/intracranial tumors to evaluate efficacy of single-agent and dual-agent treatment with selective ERK inhibitor LY3214996 (LY321) and anti-PD-1 antibody. We verified target inhibition and drug delivery and investigated treatment-induced changes in T cell response and tumor-immune microenvironment using high-parameter flow cytometry, multiplex immunoassays and T cell receptor profiling. We found that dual treatment with LY321 and anti-PD-1 significantly improved overall survival in two BRAFV600E-mutant murine melanoma models but not in KRAS-mutant murine lung adenocarcinoma. We demonstrate that although LY321 has limited blood brain barrier (BBB) permeability, combined LY321 and anti-PD-1 therapy increases tumor-infiltrating CD8+ effector T cells, broadens the T cell receptor repertoire in the extracranial tumor, enriches T cell clones shared by the periphery and brain, and reduces immunosuppressive cytokines and cell populations in tumors. Despite limited BBB permeability of LY321, combination LY321 and anti-PD-1 treatment amplifies extracranial immune responses that improve intracranial disease control, highlighting the role of extracranial tumors in driving intracranial response to treatment. Combined ERK and PD-1 inhibition is a promising therapeutic approach, worthy of further investigation for patients with melanoma BM.