Mesenchymal stem cells as carriers for systemic delivery of oncolytic viruses

OBJECTIVE Delta-24-RGD is an oncolytic adenovirus that is capable of replicating in and killing human glioma cells. Although intratumoral delivery of Delta-24-RGD can be effective, systemic delivery would improve its clinical application. Bone marrow–derived human mesenchymal stem cells (BM-hMSCs) obtained from healthy donors have been investigated as virus carriers. However, it is unclear whether BM-hMSCs can be derived from glioma patients previously treated with marrow-toxic chemotherapy or whether such BM-hMSCs can deliver oncolytic viruses effectively. Herein, the authors undertook a prospective clinical trial to determine the feasibility of obtaining BM-hMSCs from patients with recurrent malignant glioma who were previously exposed to marrow-toxic chemotherapy. METHODS The authors enrolled 5 consecutive patients who had been treated with radiation therapy and chemotherapy. BM aspirates were obtained from the iliac crest and were cultured to obtain BM-hMSCs. RESULTS The patient-derived BM-hMSCs (PD-BM-hMSCs) had a morphology similar to that of healthy donor–derived BM-hMSCs (HD-BM-hMSCs). Flow cytometry revealed that all 5 cell lines expressed canonical MSC surface markers. Importantly, these cultures could be made to differentiate into osteocytes, adipocytes, and chondrocytes. In all cases, the PD-BM-hMSCs homed to intracranial glioma xenografts in mice after intracarotid delivery as effectively as HD-BM-hMSCs. The PD-BM-hMSCs loaded with Delta-24-RGD (PD-BM-MSC-D24) effectively eradicated human gliomas in vitro. In in vivo studies, intravascular administration of PD-BM-MSC-D24 increased the survival of mice harboring U87MG gliomas. CONCLUSIONS The authors conclude that BM-hMSCs can be acquired from patients previously treated with marrow-toxic chemotherapy and that these PD-BM-hMSCs are effective carriers for oncolytic viruses.

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Mesenchymal stem cells and oncolytic viruses: joining forces against cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001684 ◽

2021 ◽

Vol 9 (2) ◽

pp. e001684

Author(s):

Rafael Moreno

Keyword(s):

Stem Cells ◽

Clinical Trials ◽

Mesenchymal Stem Cells ◽

Immune System ◽

Oncolytic Viruses ◽

Immunogenic Cell Death ◽

The Past ◽

Physical Barriers ◽

Immunogenic Properties ◽

New Strategies

The development of oncolytic viruses (OVs) has increased significantly in the past 20 years, with many candidates entering clinical trials and three of them receiving approval for some indications. Recently, OVs have also gathered interest as candidates to use in combination with immunotherapies for cancer due to their immunogenic properties, which include immunogenic cell death and the possibility to carry therapeutic transgenes in their genomes. OVs transform non-immunogenic ‘cold’ tumors into inflamed immunogenic ‘hot’ tumors, where immunotherapies show the highest efficacy. However, in monotherapy or in combination with immunotherapy, OVs face numerous challenges that limit their successful application, in particular upon systemic administration, such as liver sequestration, neutralizing interactions in blood, physical barriers to infection, and fast clearance by the immune system. In this regard, the use of mesenchymal stem cells (MSCs) as cells carrier for OV delivery addresses many of these obstacles acting as virus carriers and factories, expressing additional transgenes, and modulating the immune system. Here, I review the current progress of OVs-loaded MSCs in cancer, focusing on their interaction with the immune system, and discuss new strategies to improve their therapeutic efficacy.

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Transduction of Bone-Marrow-Derived Mesenchymal Stem Cells by Using Lentivirus Vectors Pseudotyped with Modified RD114 Envelope Glycoproteins

Journal of Virology ◽

10.1128/jvi.78.3.1219-1229.2004 ◽

2004 ◽

Vol 78 (3) ◽

pp. 1219-1229 ◽

Cited By ~ 96

Author(s):

Xian-Yang Zhang ◽

Vincent F. La Russa ◽

Jakob Reiser

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Ex Vivo ◽

Leukemia Virus ◽

Human Mscs ◽

Systemic Delivery ◽

Endogenous Virus ◽

Hiv 1

ABSTRACT Bone-marrow-derived mesenchymal stem cells (MSCs) have attracted considerable attention as tools for the systemic delivery of therapeutic proteins in vivo, and the ability to efficiently transfer genes of interest into such cells would create a number of therapeutic opportunities. We have designed and tested a series of human immunodeficiency virus type 1 (HIV-1)-based vectors and vectors based on the oncogenic murine stem cell virus to deliver and express transgenes in human MSCs. These vectors were pseudotyped with either the vesicular stomatitis virus G (VSV-G) glycoprotein (GP) or the feline endogenous virus RD114 envelope GP. Transduction efficiencies and transgene expression levels in MSCs were analyzed by quantitative flow cytometry and quantitative real-time PCR. While transduction efficiencies with virus particles pseudotyped with the VSV-G GP were found to be high, RD114 pseudotypes revealed transduction efficiencies that were 1 to 2 orders of magnitude below those observed with VSV-G pseudotypes. However, chimeric RD114 GPs, with the transmembrane and extracellular domains fused to the cytoplasmic domain derived from the amphotropic Moloney murine leukemia virus 4070A GP, revealed about 15-fold higher titers relative to the unmodified RD114 GP. The transduction efficiencies in human MSCs of HIV-1-based vectors pseudotyped with the chimeric RD114 GP were similar to those obtained with HIV-1 vectors pseudotyped with the VSV-G GP. Our results also indicate that RD114 pseudotypes were less toxic than VSV-G pseudotypes in human MSC progenitor assays. Taken together, these results suggest that lentivirus pseudotypes bearing alternative Env GPs provide efficient tools for ex vivo modification of human MSCs.

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Correction: Mesenchymal stem cells and oncolytic viruses: joining forces against cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001684corr1 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1-1

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Oncolytic Viruses

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Mesenchymal Stem Cells Mediated Drug Delivery in Tumor-Targeted Therapy

Current Drug Delivery ◽

10.2174/1567201817999200819140912 ◽

2020 ◽

Vol 17 ◽

Author(s):

Mengying Xie ◽

Lei Tao ◽

Ziqi Zhang ◽

Wei Wang

Keyword(s):

Drug Delivery ◽

Stem Cells ◽

Clinical Trials ◽

Mesenchymal Stem Cells ◽

Targeted Therapy ◽

Cancer Therapy ◽

Tumor Cells ◽

Therapeutic Agents ◽

Oncolytic Viruses ◽

Tumor Tropism

: Mesenchymal stem cells (MSCs) possess unique properties that make them potential carriers for cancer therapy. MSCs have been documented to have low immunogenicity, positive safety in clinical trials, and the ability to selectively homing to inflammation and tumor sites. Thisreview aims to introduce tumor tropism mechanism and effects of MSCs on tumor cells, and give an overview of MSCs in delivering gene therapeutic agents, oncolytic viruses and chemotherapeutics, as well as the application of MSCs-derived exosomes in tumor-targeted therapy.

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The Role Of Intra-Tracheal Versus Systemic Delivery Of Mesenchymal Stem Cells During Recovery And Resolution Following Ventilator Induced Lung Injury

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a4973 ◽

2012 ◽

Cited By ~ 1

Author(s):

Gerard Curley ◽

Bilal M. Ansari ◽

Mairead Hayes ◽

Daniel O'Toole ◽

John G. Laffey

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Lung Injury ◽

Systemic Delivery ◽

Ventilator Induced Lung Injury

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Fe3O4@polydopamine Nanoparticle-Labeled Umbilical Cord Mesenchymal Stem Cells Arrest Intervertebral Disc Degeneration by Enhancing Cell Migration

10.21203/rs.3.rs-147494/v1 ◽

2021 ◽

Author(s):

Meng Zhang ◽

Butain Zhang ◽

Ran Li ◽

Te Liu ◽

Jun Zhang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Intervertebral Disc ◽

Umbilical Cord ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Type Ii Collagen ◽

Systemic Delivery ◽

Cell Therapies

Abstract Cell therapies for intervertebral disc degeneration (IDD) are intended to replace lost intervertebral disc (IVD) cells. The key to this treatment is to promote the migration of transplanted cells to the lesion site. The purpose of this study was to evaluate the repair effect of umbilical cord mesenchymal stem cells (UCMSCs) labeled with Fe3O4@polydopamine nanoparticles (Fe3O4@PDA NPs) on rat caudal vertebra disc degeneration. We characterized UCMSCs labeled with Fe3O4@PDA NPs, analyzed the effects of nanoparticles on UCMSCs and evaluated UCMSCs labeled with Fe3O4@PDA NPs to repair IDD in vivo. We found that UCMSC Fe3O4@PDA NPs could enhanced the migration of UCMSCs by up-regulating the expression of CXC chemokine receptor type 4 (CXCR4) without effecting UCMSC functionality and the Fe3O4@PDA NPs-labeled UCMSC group had better disc height, better tissue morphology performance and a higher number of transplanted cells and induced notably better regeneration of IVD, evidenced by the higher expression of aggrecan, type II collagen, and Sox-9 and lower expression of Mmp-13, Tnf-α and Il-1β at both mRNA and protein levels than the unlabeled group. We demonstrated systemic delivery of UCMSCs labeled with Fe3O4@PDA NPs could be an appropriate protocol for accelerating and optimizing clinically applicable UCMSC treatment for IDD.

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Canine Adipose-Derived Mesenchymal Stem Cells (cAdMSCs) as a “Trojan Horse” in Vaccinia Virus Mediated Oncolytic Therapy against Canine Soft Tissue Sarcomas

Viruses ◽

10.3390/v12070750 ◽

2020 ◽

Vol 12 (7) ◽

pp. 750

Author(s):

Ivan Petrov ◽

Ivaylo Gentschev ◽

Anna Vyalkova ◽

Mohamed I. Elashry ◽

Michele C. Klymiuk ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Soft Tissue ◽

Vaccinia Virus ◽

Soft Tissue Sarcomas ◽

Trojan Horse ◽

Myxoma Virus ◽

Oncolytic Viruses ◽

Host Immune System ◽

Oncolytic Therapy

Several oncolytic viruses (OVs) including various human and canine adenoviruses, canine distemper virus, herpes-simplex virus, reovirus, and members of the poxvirus family, such as vaccinia virus and myxoma virus, have been successfully tested for canine cancer therapy in preclinical and clinical settings. The success of the cancer virotherapy is dependent on the ability of oncolytic viruses to overcome the attacks of the host immune system, to preferentially infect and lyse cancer cells, and to initiate tumor-specific immunity. To date, several different strategies have been developed to overcome the antiviral host defense barriers. In our study, we used canine adipose-derived mesenchymal stem cells (cAdMSCs) as a “Trojan horse” for the delivery of oncolytic vaccinia virus Copenhagen strain to achieve maximum oncolysis against canine soft tissue sarcoma (CSTS) tumors. A single systemic administration of vaccinia virus-loaded cAdMSCs was found to be safe and led to the significant reduction and substantial inhibition of tumor growth in a CSTS xenograft mouse model. This is the first example that vaccinia virus-loaded cAdMSCs could serve as a therapeutic agent against CSTS tumors.

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