Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 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 and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1–dependent suppressive TAM. Forty-seven patients were enrolled. No unexpected toxicities were observed, one (2%) high microsatellite instability CRC patient had a partial response, and seven (15%) patients experienced stable disease as their best response. Increase of CSF-1 concentrations and decrease of CD14 low CD16 high monocytes in peripheral blood mononuclear cells (PBMCs) confirmed CSF-1R engagement. Treatment decreased blood dendritic cell (DC) subsets and impaired IFN-λ/IL-29 production by type 1 conventional DCs in ex vivo TLR3-stimulated PBMCs. Pexidartinib also targets c-KIT and FLT3, both key growth factor receptors of DC development and maturation. In patients, FLT3-L concentrations increased with pexidartinib treatment, and AKT phosphorylation induced by FLT3-L ex vivo stimulation was abrogated by pexidartinib in human blood DC subsets. In addition, pexidartinib impaired the FLT3-L– but not GM-CSF–dependent generation of DC subsets from murine bone marrow (BM) progenitors in vitro and decreased DC frequency in BM and tumor-draining lymph node in vivo. Our results demonstrate that pexidartinib, through the inhibition of FLT3 signaling, has a deleterious effect on DC differentiation, which may explain the limited antitumor clinical activity observed in this study. This work suggests that inhibition of FLT3 should be considered when combining TKIs with immune checkpoint inhibitors.

中文翻译：

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CSF-1R抑制剂pexidartinib影响FLT3依赖性DC分化，并可能拮抗durvalumab对晚期癌症患者的作用

肿瘤相关巨噬细胞 (TAM) 是抵抗 PD-1/PD-L1 阻断的关键决定因素。这项 1 期研究（MEDIPLEX，NCT02777710）研究了 pexidartinib（一种 CSF-1R 靶向酪氨酸激酶抑制剂 (TKI)）和 durvalumab（抗 PD-L1）在晚期结直肠癌和胰腺癌患者中的安全性和有效性，目的通过消除 CSF-1 依赖性抑制 TAM 来增强对 PD-L1 阻断的反应。共招募了 47 名患者。没有观察到意外的毒性，一名 (2%) 高度微卫星不稳定性 CRC 患者出现部分缓解，七名 (15%) 患者的最佳缓解是疾病稳定。CSF-1 浓度增加和 CD14 减少低的CD16高的外周血单核细胞 (PBMC) 中的单核细胞证实了 CSF-1R 的参与。治疗减少了血液树突状细胞 (DC) 亚群，并损害了离体 TLR3 刺激的 PBMC 中 1 型常规 DC 的 IFN-λ/IL-29 产生。Pexidartinib 还针对 c-KIT 和 FLT3，这两种是 DC 发育和成熟的关键生长因子受体。在患者中，pexidartinib 治疗后 FLT3-L 浓度增加，并且在人血液 DC 亚群中，pexidartinib 消除了 FLT3-L 离体刺激诱导的 AKT 磷酸化。此外，pexidartinib 在体外损害了小鼠骨髓 (BM) 祖细胞中 FLT3-L 依赖性的 DC 亚群的生成，但不损害 GM-CSF 依赖性的生成，并降低了体内 BM 和肿瘤引流淋巴结中 DC 的频率。我们的结果表明，pexidartinib 通过抑制 FLT3 信号传导，对 DC 分化产生有害影响，这可能解释了本研究中观察到的有限抗肿瘤临床活性。这项工作表明，当 TKI 与免疫检查点抑制剂联合使用时，应考虑抑制 FLT3。