Conditionally Replicative Adenovirus as a Therapy for Malignant Peripheral Nerve Sheath Tumors
BACKGROUND: Conditionally replicative adenoviruses (CRAds) preferentially infect and lyse tumor cells. While CRAds have been clinically applied, their potential for neurofibromatosis type-1 associated malignant peripheral nerve sheath tumors (MPNSTs) remains unexplored. This study evaluates Cyclooxygenase 2 (COX2)-driven CRAds as a therapy for MPNST. METHODS: Viruses with wild type (WT) and modified fiber-knob domains were assessed for binding efficiency to the MPNST models. Viral infectivity, spread, and susceptibility of MPNST cells to oncolytic adenoviruses were assessed using both WT viruses or engineered CRAd constructs, with cell viability quantification. Tumor growth rates and survival probability of mice bearing human tumor xenografts or syngeneic allografts were assessed using intratumoral injections of CRAds. RESULTS: RGD-modified fibers exhibited improved binding to MPNST cells compared to non-cancer Schwann cells. vectors effectively replicated and lysed MPNST cells, displaying enhanced selectivity towards transformed cells. Tumor-bearing immunodeficient mice survived significantly longer when injected with CRAds compared to PBS controls, and immunocompetent models demonstrate robust infiltration of CD8+ T-cells. CONCLUSIONS: CRAds demonstrate selective binding and efficient replication in MPNST cells, leading to tumor cell lysis while sparing non-cancerous cells. These results suggest that oncolytic adenoviruses may have the potential as novel agents for MPNST therapy and thus warrant further investigation. Overall design: Syngeneic mouse allografts were established in a to compare the impact of CRAds on tumor growth. RNAseq was performed on these samples to understand the transcriptomic effects of the CRAds within allografts. Additionally, mouse nerve and liver RNAseq samples were taken for comparison. Whole Exome Sequencing was conducted on the cell lines of origin for the syngeneic allografts.