Mesenchymal Stem Cells as Vehicles for Delivering Therapeutics and Oncolytic Viruses

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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Characterization of patient-derived bone marrow human mesenchymal stem cells as oncolytic virus carriers for the treatment of glioblastoma

Journal of Neurosurgery ◽

10.3171/2021.3.jns203045 ◽

2021 ◽

pp. 1-11

Author(s):

Yuzaburo Shimizu ◽

Joy Gumin ◽

Feng Gao ◽

Anwar Hossain ◽

Elizabeth J. Shpall ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Human Mesenchymal Stem Cells ◽

Oncolytic Viruses ◽

In Vivo Studies ◽

Systemic Delivery ◽

Previously Treated

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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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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Mesenchymal stem cells as carriers for systemic delivery of oncolytic viruses

European Journal of Pharmacology ◽

10.1016/j.ejphar.2020.172991 ◽

2020 ◽

Vol 874 ◽

pp. 172991 ◽

Cited By ~ 5

Author(s):

Agata Hadryś ◽

Aleksander Sochanik ◽

Grant McFadden ◽

Joanna Jazowiecka-Rakus

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Oncolytic Viruses ◽

Systemic Delivery

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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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Cross Talk of Macrophages with Tumor Microenvironment Cells and Modulation of Macrophages in Cancer by Virotherapy

Biomedicines ◽

10.3390/biomedicines9101309 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1309

Author(s):

Sarah Di Somma ◽

Fabiana Napolitano ◽

Giuseppe Portella ◽

Anna Maria Malfitano

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Microenvironment ◽

Immune Cells ◽

Tumor Response ◽

Cell Interaction ◽

Oncolytic Viruses ◽

Malignant Cells ◽

Cellular Compartments ◽

Stromal Stem Cells

Cellular compartments constituting the tumor microenvironment including immune cells, fibroblasts, endothelial cells, and mesenchymal stromal/stem cells communicate with malignant cells to orchestrate a series of signals that contribute to the evolution of the tumor microenvironment. In this study, we will focus on the interplay in tumor microenvironment between macrophages and mesenchymal stem cells and macrophages and fibroblasts. In particular, cell–cell interaction and mediators secreted by these cells will be examined to explain pro/anti-tumor phenotypes induced in macrophages. Nonetheless, in the context of virotherapy, the response of macrophages as a consequence of treatment with oncolytic viruses will be analyzed regarding their polarization status and their pro/anti-tumor response.

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