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
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: PURPOSE: Significant correlations exist between the 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. PATIENTS AND METHODS: A nonrandomized, open-label phase Ib/2 trial (NCT01596751) evaluated pexidartinib (PLX3397), 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. RESULTS: The 12-week progression-free survival rate was 36% (95% confidence interval, 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. CONCLUSIONS: These clinical and preclinical findings provide rationale for therapies to increase the therapeutic index of αPD-1 therapy by diminishing the presence of T cell-suppressive myelomonocytic cells to improve outcomes for patients with refractory disease.
Source: Clinical Cancer Research
Authors: Amanda Poissonnier, Hope S. Rugo, Wesley Horton, Tina Kim, Amy DeLuca, Eivind Valen Egeland, Tiziana Cotechini, Shamilene Sivagnanam, Motomi Mori, Yun Yu, Byung Park, Nicky Beelen, Dhaarini Murugan, Nell Kirchberger, Shivaani Kummar, Ingrid A. Mayer, Kimberly Blackwell, E. Shelley Hwang, Lisa M. Coussens
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Funders: Center for Cancer Research, U.S. Department of Defense, Susan G. Komen for the Cure, National Foundation for Cancer Research, Carol M. Baldwin Breast Cancer Research Fund, Oregon Health and Science University, Susan G. Komen, National Institutes of Health, Knight Cancer Institute, Oregon Health and Science University, National Cancer Institute, Congressionally Directed Medical Research Programs
Awards: G1067399340, G110816805, G1581679921, G1895885240, G246298631, G2535433541, G2622222925, G2632474486, Modulating Immune Response to Improve Therapy for Breast Cancer, G3780238105, G4119534169, G4297529078, G4629423607, G515006066, Relieving Immune-Suppressive Pathways in Breast Cancer to Improve Outcomes, G5795248759, G5850682332, Regulating the Immune Microenvironment in Breast Cancer, G6758359834, G6930272016, G7141288440, G7435138590, G7448966117, G8081300246, G8151877709, G8513373206, Breast Pre-Cancer Atlas Center, Identify Molecular Predictors of Risk to Objectively Validate Evolution of DCIS (IMPROVE DCIS), G9000044262, G9000053116, G9000102471, G9000156400
OpenAlex ID: W7141651103