Multi-modal Potentiation of Oncolytic Virotherapy by Vanadium Compounds

Abstract

Oncolytic viruses (OV) are an emerging class of anticancer bio-therapeutics that induce antitumor immunity through selective replication in tumor cells. However, the efficacy of OVs as single agents remains limited. We introduce a strategy that boosts the therapeutic efficacy of OVs by combining their activity with immuno-modulating, small molecule protein tyrosine phosphatase inhibitors. We report that vanadium-based phosphatase inhibitors enhance OV infection in vitro and ex vivo, in resistant tumor cell lines. Furthermore, vanadium compounds increase antitumor efficacy in combination with OV in several syngeneic tumor models, leading to systemic and durable responses, even in models otherwise refractory to OV and drug alone. Mechanistically, this involves subverting the antiviral type I IFN response toward a death-inducing and pro-inflammatory type II IFN response, leading to improved OV spread, increased bystander killing of cancer cells, and enhanced antitumor immune stimulation. Overall, we showcase a new ability of vanadium compounds to simultaneously maximize viral oncolysis and systemic anticancer immunity, offering new avenues for the development of improved immunotherapy strategies.

Decavanadate Salts of Cytosine and Metformin: A Combined Experimental-Theoretical Study of Potential Metallodrugs Against Diabetes and Cancer

“…In this sense, vanadium species like vanadate, (H 2 VO 4 ) − , can adopt a stable trigonal-bipyramidal geometry similar to that of phosphate transition state in phosphate-metabolizing enzymes, and inhibit its biological activity (Costa-Pessoa et al, 2015 ; Crans, 2015 ; Dorsey et al, 2018 ). Since most of the enzymes inhibited by vanadate participate in key intracellular signaling processes, vanadium has been considered a transition element with relevant medicinal applications (Rehder, 2015a , b ; Del Carpio et al, 2018 ; Selman et al, 2018 ).…”

Decavanadate Inhibits Mycobacterial Growth More Potently Than Other Oxovanadates

“…Vanadium derivatives have been considered as therapeutic agents since 1899 (Lyonnet et al, 1899 ; Crans et al, 2018 ). Recent studies demonstrate that vanadium compounds and salts are effective antidiabetic agents (Sakurai, 2002 ; Thompson and Orvig, 2006 ; Kiss et al, 2008 ; Smith et al, 2008 ; Thompson et al, 2009 ; Willsky et al, 2011 , 2013 ; Crans, 2015 ; Trevino et al, 2015 ; Boulmier et al, 2017 ; Levina and Lay, 2017b ) but their therapeutic properties have been expanded for these materials to be anticancer agents (Lu and Zhu, 2011 ; Leon et al, 2017 ; Medina et al, 2017 ; Crans et al, 2018 ), immunotherapy agents (Lu and Zhu, 2011 ; Selman et al, 2018 ) as well as treatment for other diseases (Zwolak, 2014 ; Pessoa et al, 2015 ). Many of the compounds are coordination complexes, which form vanadate during processing after administration (Thompson et al, 2009 ; Willsky et al, 2011 ).…”

The First-Row Transition Metals in the Periodic Table of Medicine

“…Both vanadate and vanadyl sulfate as well as one coordination complex, bis(ethylmaltolato)oxovanadium(IV), have been investigated for potential treatment against diabetes in Phase I and II clinical trials [69,74,75]. Vanadium coordination complexes also have activities as anticancer compounds [76,77], and recently both salts and select complexes were found to enhance an oncolytic virus, VSV∆51, in combatting cancers that are resistant to existing therapeutics [78,79].…”