Losartan blocks osteosarcoma-elicited monocyte recruitment, and combined with the kinase inhibitor toceranib, exerts significant clinical benefit in canine metastatic osteosarcoma.

Purpose 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. Experimental design CCL2 expression, monocyte infiltration, and monocyte-recruitment by human and canine OS tumors and cell lines was assessed by gene expression, ELISA, and transwell migration assays. Safety and efficacy of losartan-toceranib therapy was evaluated in 28 dogs with lung metastatic osteosarcoma. Losartan PK and monocyte PD responses were assessed in three dose cohorts of dogs by chemotaxis, plasma CCL2 and multiplex cytokine assays, and RNAseq of losartan-treated human PMBCs. Results 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 ten-fold-higher dose than typical anti-hypertensive 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. Conclusions 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 pediatric osteosarcoma patients.