Conditionally replicative adenovirus as a therapy for malignant peripheral nerve sheath tumors.

Oncolytic adenoviruses (Ads) stand out as a promising strategy for the targeted infection and lysis of tumor cells, with well-established clinical utility across various malignancies. This study delves into the therapeutic potential of oncolytic Ads in the context of neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs). Specifically, we evaluate conditionally replicative adenoviruses (CRAds) driven by the cyclooxygenase 2 (COX2) promoter, as selective agents against MPNSTs, demonstrating their preferential targeting of MPNST cells compared with non-malignant Schwann cell control. COX2-driven CRAds, particularly those with modified fiber-knobs exhibit superior binding affinity toward MPNST cells and demonstrate efficient and preferential replication and lysis of MPNST cells, with minimal impact on non-malignant control cells. In vivo experiments involving intratumoral CRAd injections in immunocompromised mice with human MPNST xenografts significantly extend survival and reduce tumor growth rate compared with controls. Moreover, in immunocompetent mouse models with MPNST-like allografts, CRAd injections induce a robust infiltration of CD8+ T cells into the tumor microenvironment (TME), indicating the potential to promote a pro-inflammatory response. These findings underscore oncolytic Ads as promising, selective, and minimally toxic agents for MPNST therapy, warranting further exploration.

Viral Shedding in Mice following Intravenous Adenovirus Injection: Impact on Biosafety Classification.

There have been numerous advances in gene therapy and oncolytic virotherapy in recent years, especially with respect to cutting-edge animal models to test these novel therapeutics. With all of these advances, it is important to understand the biosafety risks of testing these vectors in animals. We performed adenovirus-based viral shedding studies in murine models to ascertain when it is appropriate to downgrade the animals from Biosafety Level (BSL) 2 to BSL 1 for experimental handling and transport. We utilized intravenous injections of a replication-competent adenovirus and analyzed viral shedding via the collection of buccal and dermal swabs from each animal, in addition to obtaining urine and stool samples. The adenovirus hexon copy number was determined by qPCR, and plaque formation was analyzed to assess the biologic activity of viral particles. Our results demonstrate that after 72 h following viral inoculation, there is no significant quantity of biologically active virus shedding from the animals. This observation suggests that on day 4 following adenovirus injection, mice can be safely downgraded to BSL 1 for the remainder of the experiment with no concern for hazardous exposure to laboratory personnel.