Anti-CSF-1R therapy with combined immuno-chemotherapy coordinate an adaptive immune response to eliminate macrophage enriched triple negative breast cancers

TL;DR

A new combination therapy for metastatic triple negative breast cancer boosts immune response and reduces recurrence by targeting macrophages and enhancing T and B cell infiltration.

Contribution

A novel immuno-chemotherapy regimen combining anti-CSF-1R, low-dose cyclophosphamide, and anti-PD-1 is effective in macrophage-rich TNBC models.

Findings

Combining anti-CSF-1R, cyclophosphamide, and anti-PD-1 significantly reduces tumor growth in aggressive TNBC models.

CSF-1R inhibition and cyclophosphamide increase infiltration of B and T cells by upregulating IL-17, IL-5, and type II interferon.

Anti-PD-1 maintenance reduces recurrence linked to PD-L1 heterogeneity in metastatic TNBC.

Abstract

Women diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory low-dose Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic Trp53 null TNBC transplantable syngeneic models that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along with CTX disrupted the M-CSF/CSF-1R axis which upregulated IL-17, IL-5 and type II interferon resulting in elevated B- and T cell infiltration. Addition of an anti-PD-1 maintenance dose helped overcome de novo PD-L1 intra-tumoral heterogeneity (ITH) associated recurrence in lung and liver mTNBC.

Metastatic triple negative breast cancer (mTNBC) has limited treatments options. Here, this group presents a combination of low-dose cyclophosphamide, anti-CSF1R, and anti-PD-1 therapies to boost immune cell infiltration and reduce recurrence in aggressive TNBC models.

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