Losartan Blocks Osteosarcoma-Elicited Monocyte Recruitment, and Combined With the Kinase Inhibitor Toceranib, Exerts Significant Clinical Benefit in Canine Metastatic Osteosarcoma.
Losartan Blocks Osteosarcoma-Elicited Monocyte Recruitment, and Combined With the Kinase Inhibitor Toceranib, Exerts Significant Clinical Benefit in Canine Metastatic Osteosarcoma.
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DOI：
10.1158/1078-0432.ccr-21-2105
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发表时间：
2022-02-15
期刊：
影响因子：
--
通讯作者：
Dow SW
中科院分区：
文献类型：
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作者：
Regan DP;Chow L;Das S;Haines L;Palmer E;Kurihara JN;Coy JW;Mathias A;Thamm DH;Gustafson DL;Dow SW
越来越多的人认识到，通过评估自发性癌症犬的免疫治疗，可以加速免疫肿瘤学的进展。骨肉瘤（OS）是一种使用免疫检查点抑制剂观察到有限临床获益的肿瘤。我们先前报道了血管紧张素受体阻断剂氯沙坦通过阻断CCL2-CCR2单核细胞募集来抑制临床前小鼠模型中的转移。在这里，我们利用自发OS的狗来确定氯沙坦的安全性和与单核细胞药效学终点相关的药代动力学，并评估其与激酶抑制剂toceranib联合使用的抗肿瘤活性。通过基因表达、ELISA和transwell迁移试验评估人和犬OS肿瘤和细胞系的CCL2表达、单核细胞浸润和单核细胞募集。在28只患有肺转移性OS的狗中评价了氯沙坦-托西拉尼治疗的安全性和有效性。通过趋化性、血浆CCL2和多重细胞因子测定以及氯沙坦治疗的人外周血单核细胞的RNA-seq，在三个剂量队列的狗中评估了氯沙坦PK和单核细胞PD反应。人和犬OS细胞分泌CCL 2并引起单核细胞迁移，这被氯沙坦抑制。犬中的氯沙坦PK/PD研究显示，阻断单核细胞迁移需要比典型抗高血压剂量高10倍的剂量。高剂量氯沙坦和toceranib治疗耐受性良好，在肺转移犬中诱导的临床获益率为50%。氯沙坦抑制CCL2-CCR2轴，并与toceranib联合使用，在转移性骨肉瘤犬中发挥显著的生物活性，支持该药物组合在儿科骨肉瘤患者中的评价。 参见韦斯等人的相关评论，
There is increasing recognition that progress in immuno-oncology could be accelerated by evaluating immune-based therapies in dogs with spontaneous cancers. Osteosarcoma (OS) is one tumor for which limited clinical benefit has been observed with the use of immune checkpoint inhibitors. We previously reported the angiotensin receptor blocker losartan suppressed metastasis in preclinical mouse models through blockade of CCL2–CCR2 monocyte recruitment. Here we leverage dogs with spontaneous OS to determine losartan's safety and pharmacokinetics associated with monocyte pharmacodynamic endpoints, and assess its antitumor activity, in combination with the kinase inhibitor toceranib. CCL2 expression, monocyte infiltration, and monocyte recruitment by human and canine OS tumors and cell lines were assessed by gene expression, ELISA, and transwell migration assays. Safety and efficacy of losartan-toceranib therapy were evaluated in 28 dogs with lung metastatic OS. Losartan PK and monocyte PD responses were assessed in three dose cohorts of dogs by chemotaxis, plasma CCL2, and multiplex cytokine assays, and RNA-seq of losartan-treated human peripheral blood mononuclear cells. Human and canine OS cells secrete CCL2 and elicit monocyte migration, which is inhibited by losartan. Losartan PK/PD studies in dogs revealed that a 10-fold-higher dose than typical antihypertensive dosing was required for blockade of monocyte migration. Treatment with high-dose losartan and toceranib was well-tolerated and induced a clinical benefit rate of 50% in dogs with lung metastases. Losartan inhibits the CCL2–CCR2 axis, and in combination with toceranib, exerts significant biological activity in dogs with metastatic osteosarcoma, supporting evaluation of this drug combination in patients with pediatric osteosarcoma. See related commentary by Weiss et al.,