Armed oncolytic viruses are an emerging therapeutic strategy for many cancers. The parvoviruses are the smallest viruses currently being developed as oncotherapeutic agents, and are non-enveloped and extremely rugged, simplifying their production, purification and storage, as well as enhancing their tissue penetration properties. Rodent protoparvoviruses can infect human cells only if neoplastically transformed, and thus are intrinsically oncotropic - the rodent protoparvovirus H-1 is currently in Phase I/IIA clinical trials against glioblastomaandpancreaticcancer.Wehavedevelopedareplicating,butnon-propagating,parvoviralvector system, which can be packaged into tumor cell target-enhanced capsid selected in vitro. These dual transgene vectors express secreted, soluble versions of murine or human PD-1 (sPD-1), or an anti-CTLA-4 camelidnanobody,coordinatelywiththemurineco-stimulatorymoleculesCD80orCD48,torenderthetumor cellitselfaneffectiveantigenpresentingcell.Wewilltestthehypothesisthatthesecretedtransgeneproducts will effectively block the two major immune checkpoint pathways when secreted directly within the tumor microenvironment, potentially avoiding the side-effects associated with systemic administration of immune checkpointinhibitors.
Melanoma is a prevalent, deadly disease with poor outcomes following metastasis. Recently developed monoclonal antibody treatments have been dramatically effective in treating metastatic melanoma by blocking inhibitory immune signals such as the CTLA-4:CD80 and/or PD-1:PDL-1 axes. To be effective, these biologics have to be administered systemically at high doses, and therefore carry the risk of inducing severe side-effects due to disruption of immune homeostasis in non-tumor tissues. To overcome these problems, we have developed replicating, but non-propagating vectors based on non-pathogenic rodent parvovirus genomes, that are capable of targeting tumor cells and delivering locally high doses of these immune checkpoint inhibitors within the tumor microenvironment. In addition, these vectors have been engineered to directly activate naive CD8+ T cells cognate for tumor-associated antigens, thus enhancing the overall anti-tumor immune response.
