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Proc Natl Acad Sci U S A. 2017 Jul 25;114(30):E6157-E6165. doi: 10.1073/pnas.1700363114. Epub 2017 Jul 14.

Stem cell-released oncolytic herpes simplex virus has therapeutic efficacy in brain metastatic melanomas.

Author information

1
Center for Stem Cell Therapeutics and Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
2
Center for Stem Cell Therapeutics and Imaging Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
3
Department of Pathology, Yale School of Medicine, New Haven, CT 06520.
4
Department of Dermatology, Yale School of Medicine, New Haven, CT 06520.
5
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
6
Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
7
Center for Stem Cell Therapeutics and Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; kshah@bwh.harvard.edu.
8
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
9
Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138.

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.

KEYWORDS:

imaging; metastasis; oncolytic virus; stem cells; tumors

PMID:
28710334
PMCID:
PMC5544283
DOI:
10.1073/pnas.1700363114
[Indexed for MEDLINE]
Free PMC Article

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