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

John D Christie,Kenneth Lowe,Alexandra R Lucas,Grant Mcfadden,Nicole Appel,Joseph N Blattman,Juliane Daggett-Vondras,Jacquelyn Kilbourne,Masmudur M Rahman,Natalie Elliott,Liqiang Zhang

doi:10.3390/cancers14020337

Abstract

Simple SummaryCancer 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.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.

Highlights

Lung metastatic tumors represent a major challenge for the clinical treatment of cancer
This study showed that anti-PD-L1 and vMyx-hTNF each can act as successful monotherapies for lung metastatic osteosarcoma, but only if animals are treated relatively early after tumor seeding
We report that myxoma virus (MYXV) armed with murine LIGHT (TNF Superfamily member 14: TNFSF14) is a positive hit in the K7M2-luc lung metastatic osteosarcoma model but possesses even more potent anti-cancer activities against advanced later-stage disease than vMyx-hTNF

Summary

Introduction

Lung metastatic tumors represent a major challenge for the clinical treatment of cancer. Estimates across many studies of patients with tumors that form outside the lung have found that 20 to 50% will eventually have lung metastasis of their disease Current treatments for lung metastatic tumors include radiation, chemotherapy, surgical resection, and immunotherapies, usually used in combination, and with varying degrees of success. Patients diagnosed with lung metastatic osteosarcoma have less than a 30% rate of survival at 5 years after diagnosis. This is because of limitations of current treatment methods, which rely on the use of high-dose combinations of chemotherapy and surgical resection of lung metastases.

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