Antitumor Effect and Immunomodulatory Mechanism of “Oncolytic Extracellular Vesicles”

Enhancing the antitumor immune response and targeting ability of oncolytic viruses will improve the effect of tumor immunotherapy. Through infecting neural stem cells (NSCs) with a capsid dual-modified oncolytic adenovirus (CRAd), we obtained and characterized the “oncolytic extracellular vesicles” (CRAdEV) with improved targeted infection and tumor killing activity compared with CRAd. Both ex vivoand in vivostudies revealed that CRAdEV activated innate immune cells and importantly enhanced the immunomodulatory effect compared to CRAd. We found that CRAdEV effectively increased the number of DCs and activated CD4+and CD8+T cells, significantly increased the number and activation of B cells, and produced higher levels of tumor-specific antibodies, thus eliciting enhanced antitumor activity compared with CRAd in a B16 xenograft immunocompetent mice model. This study provides a novel approach to oncolytic adenovirus modification and demonstrates the potential of “oncolytic extracellular vesicles” in antitumor immunotherapy.