Oncolytic Vesicular Stomatitis Virus (VSV) has potent antitumor activity against multiple myeloma. Safety concerns regarding VSV-induced neurotoxicity have largely been addressed by vector design;these recombinant VSV demonstrate tumor selectivity, attenuated neurotoxicity and potent antitumor activities against syngeneic and xenogeneic tumors. In recent preclinical studies evaluating the efficacy and safety of a new recombinant VSV for intravenous myeloma therapy, we discovered significant acute toxicities associated with high dose intravenous administration of VSV. No clinical signs of neurotoxicity were seen. Instead, animals given high dose VSV intravenously exhibited signs of acute hepatotoxicity. The finding of acute hepatic dose-limiting toxicity of intravenously administered oncolytic VSV in two animal species is of major significance for the oncolytic virotherapy field and raises important translational questions. First, it is currently unclear whether the liver toxicity is caused by the physical virus particles (in which case doses should be calibrated to this parameter) or is a consequence of cell infection. Second it is currently unknown whether toxicity will be more or less severe in the presence of circulating anti-VSV antibodies. Third, it will be important to determine whether the toxicity can be ameliorated by modifying the schedule of virus administration, for example by slowing the infusion rate or by pre-dosing with a lower dose of virus, which has been proven effective in the case of adenovirus particles. Fourth, it is currently unknown whether allometric scaling of virus dosing between species should be on the basis of body weight or surface area. The generally accepted view is that it should be based on weight which tracks with blood volume and hence with maximum circulating virus concentration after intravenous infusion. However, our preliminary data suggests that this accepted viewpoint is wrong and that allometric scaling of virus dose should be on the basis of surface area. To address these questions, we propose to 1) define the mechanistic basis for acute hepatotoxicity after intravenous administration of VSV in mice, 2) determine whether interspecies allometric scaling of the oncolytic virus dose should be on the basis of body weight or surface area. 3) determine whether virus predosing ameliorates the acute hepatic toxicity of VSV.
Oncolytic virotherapy using live attenuated Vesicular Stomatitis Virus (VSV) is a promising new approach for the treatment of cancer. Intravenous administration of VSV resulted in one-shot cure of established myeloma in immunocompetent mice. However, when increasingly high doses of virus were given, there were unexpected toxicities in the form of abnormal liver function tests and metabolic parameters. We suspect that these toxicities are due to interaction of viral particles with host cells. In preparation for our application to the US FDA for systemic use of VSV in cancer patients, we are proposing a thorough investigation to identify the safe starting dose in multiple animal species as well as develop strategies to ameliorate toxicities associated with high dose IV VSV delivery.
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