PDF file - 653K, MDSC purity (S1); Effective Feridex labeling of MDSCs (S2); VSV does not alter the ability of MDSCs to migrate to tumor sites (S3); Antibody conjugation improves viral delivery to tumor sites (S4); VSV-MDSCs exhibit more tumor specificity than free virus (S5); VSV-MDSC treatment does not result in any appreciable neuropathological toxicity (S6); The survival curves of LLC lung cancer-bearing mice after various treatments (S7).
ARTICLE ABSTRACTOne of the several impediments to effective oncolytic virus therapy of cancer remains a lack of tumor-specific targeting. Myeloid-derived suppressor cells (MDSC) are immature myeloid cells induced by tumor factors in tumor-bearing hosts. The biodistribution kinetics of MDSC and other immune cell types in a murine hepatic colon cancer model was investigated through the use of tracking markers and MRI. MDSCs were superior to other immune cell types in preferential migration to tumors in comparison with other tissues. On the basis of this observation, we engineered a strain of vesicular stomatitis virus (VSV), an oncolytic rhabdovirus that bound MDSCs and used them as a delivery vehicle. Improving VSV-binding efficiency to MDSCs extended the long-term survival of mice bearing metastatic colon tumors compared with systemic administration of wild-type VSV alone. Survival was further extended by multiple injections of the engineered virus without significant toxicity. Notably, direct tumor killing was accentuated by promoting MDSC differentiation towards the classically activated M1-like phenotype. Our results offer a preclinical proof-of-concept for using MDSCs to facilitate and enhance the tumor-killing activity of tumor-targeted oncolytic therapeutics. Cancer Res; 73(16); 5003–15. ©2013 AACR.