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Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic
John D Christie1,2, Nicole Appel1,2, Liqiang Zhang2
1School of Life Sciences, Arizona State University, Tempe, AZ 85281, USA.
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.
Insights
Oncolytic virus therapy using mouse adenovirus MYXV armed with murine LIGHT (mLIGHT) effectively reduced lung tumors and improved survival in mice. Delivery via peripheral blood mononuclear cells (PBMCs) enhanced viral activity and cancer cell killing.
Area of Science:
- Oncolytic virotherapy
- Cancer metastasis
- Immunotherapy
Background:
- Lung metastasis presents a significant challenge in cancer research and treatment.
- Oncolytic viruses offer a novel therapeutic approach, but effective delivery and arming strategies are crucial.
- Mouse adenovirus MYXV is being explored as a potential oncolytic virus vector.
Purpose of the Study:
- To evaluate the efficacy of MYXV armed with murine LIGHT (mLIGHT) in a murine lung metastases model.
- To assess the impact of using ex vivo pre-loaded peripheral blood mononuclear cells (PBMCs) as a delivery system for the armed oncolytic virus.
- To compare the therapeutic potential of mLIGHT-armed MYXV delivered via PBMCs versus direct viral administration.
Main Methods:
- Development of an immunocompetent murine K7M2-luc lung metastases model.
- Systemic delivery of mLIGHT-armed MYXV (vMyx-mLIGHT) using ex vivo pre-loaded PBMCs.
- In vitro assessment of cytotoxic capacity against K7M2 cancer cells.
- In vivo evaluation of viral reporter transgene expression in tumors and periphery.
Main Results:
- Systemic delivery of vMyx-mLIGHT using PBMCs significantly reduced tumor burden and increased median survival time in the advanced lung metastases model.
- PBMC-loaded vMyx-mLIGHT demonstrated superior cytotoxic capacity against K7M2 cancer cells in vitro compared to free MYXV.
- In vivo administration of vMyx-mLIGHT/PBMCs led to enhanced viral reporter transgene expression in lung tumors and systemically.
Conclusions:
- mLIGHT-armed MYXV, particularly when delivered via PBMC carrier cells, shows significant therapeutic potential against solid cancers that metastasize to the lung.
- PBMC-mediated delivery enhances the efficacy of oncolytic viruses, suggesting a promising strategy for improving cancer treatment outcomes.
- This approach represents a novel therapeutic strategy for managing lung metastatic disease.
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