Title | Stem cell-released oncolytic herpes simplex virus has therapeutic efficacy in brain metastatic melanomas. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Du W, Seah I, Bougazzoul O, Choi GH, Meeth K, Bosenberg MW, Wakimoto H, Fisher D, Shah K |
Journal | Proc Natl Acad Sci U S A |
Volume | 114 |
Issue | 30 |
Pagination | E6157-E6165 |
Date Published | 2017 07 25 |
ISSN | 1091-6490 |
Keywords | Animals, Brain Neoplasms, Cell Line, Humans, Melanoma, Experimental, Mesenchymal Stromal Cells, Mice, Neoplasm Metastasis, Oncolytic Virotherapy, Oncolytic Viruses, Simplexvirus, Tumor Cells, Cultured |
Abstract | The recent Food and Drug Administration approval of immunogenic oncolytic virus (OV) has opened a new era in the treatment of advanced melanoma; however, approximately 50% of patients with melanoma develop brain metastasis, and currently there are no beneficial treatment options for such patients. To model the progression of metastases seen in patients and to overcome the hurdles of systemic delivery of OV, we developed melanoma brain metastasis models in immunocompromised and immunocompetent mice, and tested the fate and efficacy of oncolytic herpes simplex virus (oHSV)-armed mesenchymal stem cells (MSCs). Using brain-seeking patient-derived melanoma cells and real-time in vivo imaging, we show a widespread distribution of micrometastases and macrometastases in the brain, recapitulating the progression of multifoci metastases seen in patients. We armed MSCs with different oHSV variants (MSC-oHSV) and found that intracarotid administration of MSC-oHSV, but not of purified oHSV alone, effectively tracks metastatic tumor lesions and significantly prolongs the survival of brain tumor-bearing mice. In a syngeneic model of melanoma brain metastasis, a combination of MSC-oHSV and PD-L1 blockade increases IFNγ-producing CD8 tumor-infiltrating T lymphocytes and results in a profound extension of the median survival of treated animals. This study thus demonstrates the utility of MSCs as OV carriers to disseminated brain lesions, and provides a clinically applicable therapeutic platform to target melanoma brain metastasis. |
DOI | 10.1073/pnas.1700363114 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 28710334 |
PubMed Central ID | PMC5544283 |
Grant List | P01 CA163222 / CA / NCI NIH HHS / United States R01 CA204720 / CA / NCI NIH HHS / United States |
Submitted by kej2006 on June 6, 2018 - 4:12pm