Stem Cells Loaded With Multimechanistic Oncolytic Herpes Simplex Virus Variants for Brain Tumor Therapy

Duebgen, Matthias; Martínez-Quintanilla, Jordi; Tamura, Kaoru; Hingtgen, Shawn; Redjal, Navid; Wakimoto, Hiroaki; Shah, Khalid

doi:10.1093/jnci/dju090

Cited by 104 publications

(82 citation statements)

References 37 publications

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“…Our results indicate that human MSCs loaded with different oHSV variants provide a platform to translate OV therapies to clinics in a broad spectrum of GBMs after resection and could also have direct implications in different cancer types (Duebgen et al, 2014). These studies confirm the feasibility of using MSCs as carriers for OV therapy.…”

Section: Stem Cell -Oncolytic Virus Therapysupporting

confidence: 73%

Stem Cell-Based Therapies for Cancer

Bhere

Shah

2015

Advances in Cancer Research

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Section: Stem Cell -Oncolytic Virus Therapysupporting

confidence: 73%

Stem Cell-Based Therapies for Cancer

Bhere

Shah

2015

Advances in Cancer Research

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“…Given that delivery of therapeutic agents to the tumors in the brain is a major challenge, significant efforts have been made to develop efficient delivery routes to brain tumors, which include both invasive and noninvasive administration strategies (42). In a previous study, we showed that local implantation of encapsulated MSCs loaded with oHSV have therapeutic efficacy in mouse models of resected brain tumors (21). Recent studies have shown that i.v.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies from our laboratory demonstrated that therapeutic human and mouse stem cells home extensively to multiple tumor deposits in the brain (20) and act as cell carriers for onsite delivery of tumor-specific agents or OV (21) in mouse models of different brain tumor types (22). In the present study, we tested the therapeutic efficacy of MSC-loaded oHSV (MSCoHSV) in both BRAF mutant and WT in vivo imageable mouse models of melanoma brain metastasis, and explored the combined therapeutic efficacy of PD-L1 blockade and MSC-oHSV in a syngeneic mouse model of melanoma brain metastasis.…”

Section: Significancementioning

confidence: 99%

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

Seah

Bougazzoul

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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101

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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.stem cells | oncolytic virus | tumors | metastasis | imaging M elanoma, the most aggressive type of skin cancer, accounts for a large proportion of skin cancer-related deaths (1). Among all cancer types, melanoma has a particularly high propensity to metastasize to the brain, occurring in >50% of all patients with advanced disease. More than 90% of melanoma brain metastases lead to death, and the median survival is 17-22 wk after detection (2-4).Current therapeutic options of chemotherapy, surgery, and radiation have very limited efficacy for patients with melanoma brain metastasis (5-7). These patients either have multiple metastatic lesions or diagnostically challenging asymptomatic lesions, making surgery an inadequate therapeutic option by itself. In addition, the blood-brain barrier (BBB) limits central nervous system (CNS) penetration of systemic therapies, and the negative side effects of radiotherapy (8) pose challenges for the success of existing therapies, contributing to the failure to improve overall patient survival. As such, there is an urgent need for new therapies for melanoma brain metastasis.The development and characterization of preclinical tumor models that authentically recapitulate the clinical disease settings are critical for developing and testing new therapies. Most previous studies have used either subcutaneous (s.c.) injection or intracranial injection of established melanoma lines in mice (9-11), which do not mimic the actual clinical settings of melanoma brain metastasis,...

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“…Mesenchymal Stem Cells (MSCs) loaded with oncolytic herpes simplex virus (oHSV) have recently been shown to be effective and provide a significantly higher benefit in glioma-bearing mice compared to pure oHSV [102]. Despite good preclinical results, the clinical application of stem cells as carriers of brain-targeted therapy is still controversial.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies

Mangraviti¹,

Gullotti²,

Tyler³

et al. 2016

Journal of Controlled Release

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Stem Cells Loaded With Multimechanistic Oncolytic Herpes Simplex Virus Variants for Brain Tumor Therapy

Abstract: Human MSC loaded with different oHSV variants provide a platform to translate oncolytic virus therapies to clinics in a broad spectrum of GBMs after resection and could also have direct implications in different cancer types.

Cited by 104 publications

References 37 publications

Stem Cell-Based Therapies for Cancer

Stem Cell-Based Therapies for Cancer

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

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies

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