CSF1R Inhibition with Chemotherapy Relieves Systemic Immune Suppression in Patients with Metastatic Triple-Negative Breast Cancer and Boosts anti-PD-1 Efficacy in Transgenic Mammary Tumors.

Abstract

Significant correlations exist between presence of intratumoral macrophages, tumor progression, and poor outcomes in triple-negative breast cancer (TNBC) with limited therapeutic options available for advanced stage disease. Preclinical studies revealed that inhibition of myelomonocytic colony stimulating factor 1 (CSF1) or its receptor (CSF1R), plus cytotoxic chemotherapy decreased primary tumor growth kinetics and pulmonary metastases by CD8+ T cell-dependent mechanisms. This translational study evaluated CSF1R inhibition combined with eribulin in metastatic TNBC and explored rational preclinical combination strategies with PD-1/PD-L1-blockade based on clinical immune correlate analyses. A nonrandomized, open-label phase 1b/2 trial (NCT01596751) evaluated pexidartinib (PLX3397, PLX), a CSF1R inhibitor (CSF1Ri), plus eribulin mesylate in heavily pretreated individuals with metastatic TNBC. Clinical efficacy was assessed alongside peripheral blood correlates. Preclinical studies in transgenic mammary adenocarcinoma models examined biomarker-driven therapy combinations. The 12-week progression-free survival rate was 36% (95% CI, 22.2%-58.4%), with 44.8% of patients achieving clinical benefit; a subset experienced disease control beyond 6-months. Patients with partial response or stable disease demonstrated increased baseline leukocyte activation, including enrichment of CD8+ and CD4+ memory T cells and increased PD-1 expression on CD4+ T cells. In preclinical studies, CSF1Ri expanded the therapeutic index of PD-1 blockade, yielding transient tumor regression in ~60% of mice and a transient expansion of effector and resident memory T cells. These clinical and preclinical findings provide rationale for therapies to increase therapeutic index of aPD-1 therapy by diminishing presence of T cell-suppressive myelomonocytic cells to improve outcomes for patients with refractory disease.