Intravenous HER2-Targeted Vesicular Stomatitis Virus Infects and Cures Murine Mammary Tumors and Induces Anti-tumor Memory

Background/Aim: Vesicular stomatitis virus (VSV) is a potent experimental oncolytic virus, but intravenous (IV) treatment is limited by rapid clearance and inefficient tumor delivery. This study investigated whether a HER2-targeted recombinant VSV could reach HER2-expressing tumors and produce therapeutic benefit after systemic administration. Materials and Methods: BALB/c mice bearing HER2-positive D2F2/E2 or parental D2F2 mammary tumors received a replicating recombinant VSV (rrVSV), IV rrVSV-G HER2, in which native low-density lipoprotein-receptor binding was 90% reduced by K47Q/R354Q substitutions and a HER2-specific single-chain antibody (SCA) was added to VSV-G. Tumor virus recovery, HER2 dependence, comparison with related viruses, effect of cyclophosphamide administration, survival after treatment of 3-day peritoneal tumors, and generation of anti-tumor T-cell immunity were examined. Results: Preferential virus recovery in HER2-expressing tumors was greatest 3 days following IV administration. Tumor recovery from D2F2/E2 tumors expressing HER2 was markedly greater (4,482-fold) than from parental D2F2 tumors that did not express HER2. rrVSV-G HER2 gave much higher tumor virus recovery than did wild-type VSV (286-fold), a prostate-specific membrane antigen (PSMA)-targeted control virus, or rrVSV-Sindbis HER2, an rrVSV in which the native G-glycoprotein (gp) was replaced by a targeted Sindbis gp. Treatment with IV rrVSV-G HER2 yielded cures in 44% (12 of 27) of mice bearing 3-day peritoneal D2F2/E2 tumors, when given in combination with anti-CTLA4 and cyclophosphamide. Long-term survivors developed anti-tumor T-cell immunity as shown by resistance to tumor rechallenge and the presence of HER2-specific tetramer-positive CD8+ T cells. Conclusion: Intravenously administered HER2-targeted VSV can preferentially infect HER2-expressing tumors, eliminate those tumors as part of combination immunotherapy, and generate anti-tumor memory T cells in a murine mammary tumor model.