Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases

Leoni, Valerio; Gatta, Valentina; Palladini, Arianna; Nicoletti, Giordano; Ranieri, Dario; Dall’Ora, Massimiliano; Grosso, Valentina; Rossi, Martina; Alviano, Francesco; Bonsi, Laura; Nanni, Patrizia; Lollini, Pier‐Luigi; Campadelli-Fiume, Gabriella

doi:10.18632/oncotarget.5793

Cited by 65 publications

(58 citation statements)

References 51 publications

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“…Attributed to their innate tumor tropism, stem cells carrying oHSV have been shown to target tumor lesions in the lung and prevent metastases upon i.v. injection (43). Based on previous findings and our present findings, stem cell-based oncolytic virotherapies could have the potential to be broadly applicable in targeting metastatic lesions in organs such as the liver, colon, and lung.…”

Section: Ifnγsupporting

confidence: 77%

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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.

102

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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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Section: Ifnγsupporting

confidence: 77%

“…Recent studies have shown that i.v. injected MSC-oHSV have therapeutic efficacy in treating lung metastatic tumors (43). These studies imply that i.v.-injected MSC-oHSV would be more suitable for treating both primary and metastatic tumors in the lungs as opposed to the tumors in the brain.…”

Section: Discussionmentioning

confidence: 92%

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.

102

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“…R-LM249 exerted a therapeutic effect against peritoneal and brain metastases of ovarian and breast cancers after intra-peritoneal injections [ 55 ]. R-LM249 can be administered systemically by means of carrier cells, and exerts therapeutic effects against lung and brain metastases [ 57 ]. The full retargeting observed in cell cultures holds true also in animals.…”

Section: Overview Of Tropism Retargeting Based On Modification Of mentioning

confidence: 99%

“…The use of mesenchymal stem cells as carriers of retargeted oncolytic viruses has not been attempted, likely because these cells exhibit scarse-null expression of the targeted receptors. Recently, we reported that mesenchimal stromal cells (MSCs) from different sources can be forcedly infected with an HER2-retargeted oncolytic HSV, by exposing the virion-MSC mixtures to the fusogenic agent PEG 6000 [ 57 ]. Progeny viruses spread from MSCs to cancer cells in vitro and in vivo .…”

Section: Systemic Delivery Of Retargeted Oncolytic Hsvs By Means Omentioning

confidence: 99%

“…The growth of ovarian cancer lung metastases in nude mice was strongly inhibited, and the majority of treated mice appeared metastasis-free. The treatment also significantly inhibited breast cancer metastases to the brain in the NOD scid gamma mice, and reduced by more than one-half the metastatic burden in the brain [ 57 ]. Clearly, the therapeutic effects reflected the advantages of the system, i.e.…”

Section: Systemic Delivery Of Retargeted Oncolytic Hsvs By Means Omentioning

confidence: 99%

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Retargeting Strategies for Oncolytic Herpes Simplex Viruses

Campadelli-Fiume

Petrovic

Leoni

et al. 2016

Viruses

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Most of the oncolytic herpes simplex viruses (HSVs) exhibit a high safety profile achieved through attenuation. They carry defects in virulence proteins that antagonize host cell response to the virus, including innate response, apoptosis, authophagy, and depend on tumor cell proliferation. They grow robustly in cancer cells, provided that these are deficient in host cell responses, which is often the case. To overcome the attenuation limits, a strategy is to render the virus highly cancer-specific, e.g., by retargeting their tropism to cancer-specific receptors, and detargeting from natural receptors. The target we selected is HER-2, overexpressed in breast, ovarian and other cancers. Entry of wt-HSV requires the essential glycoproteins gD, gH/gL and gB. Here, we reviewed that oncolytic HSV retargeting was achieved through modifications in gD: the addition of a single-chain antibody (scFv) to HER-2 coupled with appropriate deletions to remove part of the natural receptors’ binding sites. Recently, we showed that also gH/gL can be a retargeting tool. The insertion of an scFv to HER-2 at the gH N-terminus, coupled with deletions in gD, led to a recombinant capable to use HER-2 as the sole receptor. The retargeted oncolytic HSVs can be administered systemically by means of carrier cells-forcedly-infected mesenchymal stem cells. Altogether, the retargeted oncolytic HSVs are highly cancer-specific and their replication is not dependent on intrinsic defects of the tumor cells. They might be further modified to express immunomodulatory molecules.

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Harnessing Biology to Deliver Therapeutic and Imaging Entities via Cell‐Based Methods

Joshi

Hardie

Farkas

2018

Chemistry A European J

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The accumulation of therapeutic and imaging agents at sites of interest is critical to their efficacy. Similarly, off-target effects (especially toxicity) are a major liability for these entities. For this reason, the use of delivery vehicles to improve the distribution characteristics of bio-active agents has become ubiquitous in the field. However, the majority of traditionally employed, cargo-bearing platforms rely on passive accumulation. Even in cases where “targeting” functionalities are used, the agents must first reach the site in order for the ligand–receptor interaction to occur. The next stage of vehicle development is the use of “recruited” entities, which respond to biological signals produced in the tissues to be targeted, resulting in improved specificities. Recently, many advances have been made in the utilization of cells as delivery agents. They are biocompatible, exhibit excellent circulation lifetimes and tissue penetration capabilities, and respond to chemotactic signals. In this Minireview, we will explore various cell types, modifications, and applications where cell-based delivery agents are used.

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Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases

Cited by 65 publications

References 51 publications

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

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

Retargeting Strategies for Oncolytic Herpes Simplex Viruses

Harnessing Biology to Deliver Therapeutic and Imaging Entities via Cell‐Based Methods

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