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CSF1R Inhibition with Chemotherapy Relieves Systemic Immune Suppression in Patients with Metastatic Triple-Negative
Amanda Poissonnier1, Hope S Rugo2, Wesley Horton1
1Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon.
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.
Insights
Combining CSF1R inhibition with eribulin showed promise in metastatic triple-negative breast cancer (TNBC). This approach may enhance PD-1 blockade efficacy by reducing immunosuppressive cells, improving outcomes for refractory TNBC patients.
Area of Science:
- Oncology
- Immunology
- Translational Medicine
Background:
- Triple-negative breast cancer (TNBC) has limited treatment options for advanced stages.
- Intratumoral macrophages correlate with TNBC progression and poor outcomes.
- Inhibiting colony stimulating factor 1 receptor (CSF1R) may enhance anti-tumor immunity.
Purpose of the Study:
- To evaluate CSF1R inhibition combined with eribulin in metastatic TNBC.
- To explore preclinical combination strategies with PD-1/PD-L1 blockade.
- To analyze clinical immune correlates of response.
Main Methods:
- A nonrandomized, open-label phase 1b/2 trial of pexidartinib (CSF1Ri) plus eribulin in metastatic TNBC patients.
- Assessment of clinical efficacy and peripheral blood immune correlates.
- Preclinical studies in mouse models to examine biomarker-driven combinations.
Main Results:
- 36% 12-week progression-free survival and 44.8% clinical benefit rate in patients.
- Patients with clinical benefit showed increased baseline leukocyte activation, CD8+/CD4+ T cells, and PD-1 expression.
- Preclinical CSF1R inhibition enhanced PD-1 blockade, causing tumor regression and T cell expansion in mice.
Conclusions:
- CSF1R inhibition combined with eribulin shows clinical activity in refractory metastatic TNBC.
- Diminishing T cell-suppressive myelomonocytic cells can increase the therapeutic index of PD-1 blockade.
- These findings support further investigation of combination therapies for improved TNBC outcomes.
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