In vivo antitumor activity by dual stromal and tumor-targeted oncolytic measles viruses

Abstract

The tumor stroma acts as a barrier that limits the efficacy of systemically administered oncolytic viruses (OV). We previously demonstrated that stromal-selective, retargeted oncolytic measles viruses (MVs) delay in vivo tumor progression. To further characterize the contribution of stromal targeting to MV's overall in vivo efficacy in an experimental cancer model, a dual targeted oncolytic measles virus (MV-CD46-muPA) able to simultaneously infect murine stromal (via murine uPAR) and human cancer (via CD46) cells was developed. MV-CD46-muPA infected, replicated, and induced cytotoxicity in both murine and human cancer cells. Viral infection was successfully transferred from stromal to tumor cells in vitro, leading to tumor cell oncolysis. Systemic administration of MV-CD46-muPA led to improved antitumor effects in colon (HT-29) cancer xenografts compared to vehicle or CD46 only targeted MVs. These effects were associated with improved tumor viral deposition, increased apoptosis, and decreases in murine stromal endothelial cells and fibroblasts. MV-CD46-muPA modulated cell cycle, survival, proliferation, and metabolic pathways, as determined by functional proteomic analysis of treated tumors. The above findings further validate the concept that dual stromal and tumor cell viral targeting enhances the therapeutic effects of systemically administered OVs and support further preclinical and clinical development of stromal directed virotherapies.

MicroRNA-sensitive oncolytic measles virus for chemovirotherapy of pancreatic cancer

“… 66 , 67 With regards to MeV therapy, targeting both neoplastic cells and cells of the stromal compartment has been shown to result in superior efficacy. 68 It is conceivable that through similar mechanisms, MeV chemovirotherapy may lead to remodeling of the extracellular matrix in PDAC with positive therapeutic effects. However, in light of the functional heterogeneity among non-neoplastic cell types in PDAC tumors, outcomes of stromal targeting will need careful assessment.…”

The Urokinase Receptor (uPAR) as a “Trojan Horse” in Targeted Cancer Therapy: Challenges and Opportunities

“…In vitro, MV-h-uPA and MV-m-uPA efficiently infected, replicated, and induced cytotoxicity in uPAR-expressing tumor and stromal cells, respectively, cancer-associated fibroblasts (CAFs) and endothelial cells, compared to the normal counterparts, in a receptor- and species-specific manner [ 261 , 262 , 263 ]. Successful species-specific fibroblast to tumor cell viral transfer was also observed [ 264 ]. Accordingly, murine CAFs infection by MV-m-uPA inhibited paracrine growth of co-cultured virus insensitive human cancer cells, which was instead stimulated by uninfected CAFs [ 262 ].…”

“…Similar results were obtained in a recent follow-up study by the same group, where dual-targeted oncolytic MVs able to bind murine stromal (via murine uPAR) and human cancer (via CD46) cells were engineered and shown to successfully infect and lyse the target cells in a species-specific fashion, both in vitro and in vivo, in colon (HT-29) cancer xenografts, leading to improved tumor suppression and overall survival compared to vehicle CD46-only targeted MVs [ 264 ] ( Table 5 , Figure 12 ).…”

Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy

“…Therefore, a uPAR-retargeted MV has been designed. Virus-mediated regulation of tumor-stroma interactions, including decreased ECs and fibroblasts, and downregulated gene expression associated with stromal components and angiogenesis, have been observed in several tumor models [ 112 , 113 ]. In terms of targeting the ECM, hyaluronan is a critical ECM component responsible for tissue elasticity and water retention, which is closely related to elevated IFP in tumor stroma [ 114 ].…”