The CSF-1R inhibitor Pexidartinib impacts dendritic cell differentiation through inhibition of FLT3 signaling and may antagonize the effect of durvalumab in patients with advanced cancer – results from a phase 1 study
التفاصيل البيبلوغرافية
العنوان:
The CSF-1R inhibitor Pexidartinib impacts dendritic cell differentiation through inhibition of FLT3 signaling and may antagonize the effect of durvalumab in patients with advanced cancer – results from a phase 1 study
Tumor-associated macrophages (TAM) are critical determinant of resistance to programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) blockade. This phase I study (MEDIPLEX,NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R-directed tyrosine kinase inhibitor (TKI), and durvalumab (anti-PD-L1) in patients with advanced colorectal (CRC) and pancreatic (PDAC) carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1-dependent suppressive TAM. No unexpected toxicities were observed and 2% and 15% of patients achieved partial response and stable disease respectively. Increase of CSF-1 levels and decrease of CD14lowCD16highmonocytes in peripheral blood mononuclear cells (PBMC) confirmed CSF-1R engagement. Treatment significantly decreased blood dendritic cell (DC) subsets and impaired IFN-λ/IL-29 production by type-1 conventional DC inex vivoTLR3-stimulated PBMC. Pexidartinib also targets c-KIT and FLT3, both key growth factor receptors of DC development and maturation. In patients, FLT3-L levels increased with pexidartinib treatment.In vitro, pexidartinib impaired the FLT3-L but not GM-CSF-dependent generation of DC subsets from murine bone marrow progenitors. Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has deleterious effect on DC differentiation, which may explain the limited anti-tumor clinical activity observed in this study. This study suggests that inhibition of FLT3 should be taken into account when combining TKIs with immune checkpoint blockers.One-sentence summaryPexidartinib affects the development of dendritic cells