CSF-1R inhibitor, pexidartinib, sensitizes esophageal adenocarcinoma to PD-1 immune checkpoint blockade in a rat model

Abstract

Esophageal adenocarcinoma (EAC) is a leading cause of cancer deaths. Pexidartinib, a multi-gene tyrosine kinase inhibitor, through targeting CSF-1R, down modulates macrophage mediated pro-survival tumor signaling. Previously, CSF-1R inhibitors have successfully shown to enhance antitumor activity of PD-1/PD-L1 inhibitors by suppressing tumor immune evasion, in solid tumors. In this study, we investigated the antitumor activity of pexidartinib alone or in combination with blockade of PD-1 in a de novo EAC rat model. Here, we showed limited toxicity with significant tumor shrinkage in pexidartinib treated animals compared to controls, single agent and in combination with a PD-1 inhibitor, AUNP-12. Suppression of CSF-1/CSF-1R axis resulted in enhanced infiltration of CD3+CD8+ T cells with reduced M2 macrophage polarization, in the tumor microenvironment (TME). Endpoint tissue gene expression in pexidartinib treated animals demonstrated upregulation of BAX, Cas3, TNFα, IFNγ and IL6 and downregulation of Ki67, IL13, IL10, TGFβ and Arg1 (p<0.05). Additionally, among the pexidartinib treated animals responders compared to non-responders demonstrated a significant upregulation of pre-treatment CSF-1 gene, confirming that tumor associated macrophage suppression directly translates to clinical benefit. Moreover, a post-treatment serum cytokine assay exhibited similar systemic trends as the gene expression in the TME, depicting increases in pro-inflammatory cytokines and decreases in anti-inflammatory cytokines. In conclusion, our study established a promising combinatorial strategy using a CSF-1R inhibitor to overcome resistance to PD-1/PD-L1 axis blockade in an EAC model, providing the rationale for future clinical strategies.

Pexidartinib synergize PD-1 antibody through inhibiting treg infiltration by reducing TAM-derived CCL22 in lung adenocarcinoma

“…In Phase I clinical trial, Pexidartinib was combined with sirolimus for the treatment of unresectable Sarcoma and Malignant Peripheral Nerve Tumors ( Manji et al, 2021 ). Pexidartinib was also combined with other anti-tumor drugs like PD-1 checkpoint to approach a better outcome, in Esophageal adenocarcinoma rat model, the use of pexidartinib can improve the efficacy of PD-1 immune checkpoint, Endpoint tissue gene expression results showed that transcription levels of both TGFβ and Arg1 were significantly decreased, which was consistent with our results ( Omstead et al, 2022 ). Novel drug release strategies have also been reported to improve the effect of pexidartinib combined with PD-1 treatment ( Li et al, 2022 ).…”

Immunotherapy: Reshape the Tumor Immune Microenvironment

“…CSF-1R inhibitor overcome the resistance to PD-1/PD-L1 axis blockade in an esophageal adenocarcinoma model, resulting in enhanced T cells infiltration and reduced M2 macrophage polarization in the TIME. It confirms that the direct translation of TAM suppression into clinical benefit ( 217 ). Emactuzumab, an anti-CSF-1R antibody, has a manageable safety profile in combination with atezolizumab over atezolizumab monotherapy.…”

New insights into the role of macrophages in cancer immunotherapy

“…At present, CSF1R inhibitors in combination with chemotherapy have been tried in clinical trials in some cancers, such as localized prostate cancer and orthotopic glioblastoma ( 49 , 50 ). In addition, blocking CSF1/CSF1R can improve the efficacy of a variety of immunotherapies, including CD-40 agonists ( 51 ) and PD-1 inhibitors ( 52 ).…”