Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma

SIMPLE SUMMARY: Cancer metastasis to the lung represents the second most common site of metastasis, and a major challenge for clinical treatment of cancer, however, armed oncolytic viruses (Ovs) systemically delivered by carrier leukocytes represents a new treatment strategy. To study PBMC delivery of oncolytic myxoma virus armed with murine LIGHT (vMyx-mLIGHT), we exploited a later-stage syngeneic murine lung metastatic osteosarcoma model. Our results show that PBMC-delivered vMyx-mLIGHT is an effective treatment for even later-stage disease in vivo and offered superior tumor cell cytotoxicity in vitro. Taken together, vMyx-mLIGHT/PBMC therapy offers great promise to treat lung metastatic cancers. ABSTRACT: Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases model, the efficacy of MYXV armed with murine LIGHT (TNFSF14/CD258) expressed under virus-specific early/late promoter was tested in an advanced later-stage disease K7M2-luc model. Results in this model show that mLIGHT-armed MYXV, delivered systemically using ex vivo pre-loaded PBMCs as carrier cells, reduced tumor burden and increased median survival time. In vitro, when comparing direct infection of K7M2-luc cancer cells with free MYXV vs. PBMC-loaded virus, vMyx-mLIGHT/PBMCs also demonstrated greater cytotoxic capacity against the K7M2 cancer cell targets. In vivo, systemically delivered vMyx-mLIGHT/PBMCs increased viral reporter transgene expression levels both in the periphery and in lung tumors compared to unarmed MYXV, in a tumor- and transgene-dependent fashion. We conclude that vMyx-mLIGHT, especially when delivered using PBMC carrier cells, represents a new potential therapeutic strategy for solid cancers that metastasize to the lung.