Treatment sequence of stem cell delivered heterologous oncolytic virus impact on tumor microenvironment in immunocompetent ovarian cancer model

Vollständiger Abstract

Worum geht es in dieser Arbeit?

Introduction Ovarian cancer (OC) is a biologically heterogeneous malignancy associated with poor clinical outcomes. Oncolytic viruses (OVs) have emerged as a promising immunotherapeutic strategy; however, optimal approaches to maximize their antitumor efficacy—especially in combinatorial or sequential settings—remain insufficiently defined. To determine how the sequence of administration of two clinically relevant, stem cell–delivered OV platforms influences tumor control and immune remodeling in an immunocompetent OC model. Methods We investigated the sequence of two clinically relevant products: neural stem cell delivered conditionally replication competent adenovirus (NSC.CRAd-S-pk7; NNV24) and a mesenchymal stem cell delivered vaccinia virus (MSC.VP001; SNV1). Female C57BL/6 mice were randomized into three groups: untreated tumor-bearing controls, NNV24 followed by SNV1 (NNV24+SNV1), or SNV1 followed by NNV24 (SNV1+NNV24). Therapeutic efficacy and immune responses were assessed by overall survival, histopathological evaluation, flow cytometric analysis of dendritic cell (DC) subsets and cytotoxic T lymphocytes (CTLs), and bulk RNA sequencing. Results Treatment regimens initiated with NNV24 significantly prolonged survival compared with SNV1-first sequences. NNV24+SNV1 treatment resulted in enhanced intratumoral viral localization, increased infiltration of CTLs, mature DCs, and concomitant with a reduction in tolerogenic DC populations. Transcriptomic profiling corroborated these findings through revealing suppression of immunoregulatory and tolerogenic pathways signaling in comparison to SNV1+NNV24 group. Discussion The treatment sequence of heterologous OV has a significant effect on the tumor microenvironment. NNV24+SNV1 promotes robust antitumor immunity and improved survival, whereas the reverse sequence compromises immune activation and therapeutic response. These findings establish a mechanistic framework for rational sequencing of OV-based immunotherapies.