Abstract 5009: Deciphering anticancer mechanisms of oncolytic virus-loaded stem cells

Abstract Background: Oncolytic viruses (OVs) selectively trap, replicate, and eradicate tumor cells without endangering healthy cells. However, any virus that enters the body will be found and rendered inactive by our immune system. Therefore, cancer-killing viruses don't function properly when given by themselves. Loading therapeutic viruses into stem cells is a promising solution since they shield the OVs from the immune system until they reach tumor cells and eventually destroy them. Stem cells are potent immunomodulators and, apart from protecting and delivering the cancer-killing viruses may release additional cell factors that may regulate tumor microenvironment favoring the effect of the therapy. In this study, we analyze these factors secreted by clinically relevant stem cells loaded with oncolytic viruses CLD-101 (Neuronova platform) and CLD-201 (Supernova platform) Method: In our studies, we loaded neural stem cell line (NSCs) with tumor-selective oncolytic adenovirus CRAD-s-PK7 (CLD-101) and adipose-derived stem cells (AD-MSC) with tumor-selective oncolytic adenovirus vaccinia virus CAL1 (CLD-201), and studied their secretome transcriptomic and proteomic profile. Results: The transcriptomic analysis demonstrated that immunomodulatory cytokines, chemokines, and their receptors are induced after three and twenty-four hours of OV infection. The proteomic analysis of the virus-loaded stem cells revealed a notable distinction from the naive stem cells indicating a potential immunotherapeutic role of the stem cells in addition to the delivery and protection of the OVs. Conclusions: Our findings suggest that the enhanced therapeutic efficacy of stem cells loaded with OV is, at least partially because of qualitative and quantitative alterations in stem cells' secretome (including immunostimulatory cytokines and chemokines), These findings advance our knowledge of the molecular mechanisms underlying the immunostimulatory role of OV-loaded stem cells and specifically help to understand the mechanism of action of the promising clinical immunotherapies CLD-101 and CLD-201. Citation Format: Mohamed Hammad, Arun Seth, Yate-Ching Yuan, Hoi Wa Ngai, Rachael Mooney, Jacqueline Lara, Yunyi Kang, Ivelina Minev, Duong Hoang Nguyen, Boris Minev, Antonio Santidrian, Karen Aboody. Deciphering anticancer mechanisms of oncolytic virus-loaded stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5009.