Patient-derived mesenchymal stem cells as delivery vehicles for oncolytic virotherapy: novel state-of-the-art technology

Abstract

Oncolytic virotherapy is gaining interest in the clinic as a new weapon against cancer. In vivo administration of oncolytic viruses showed important limitations that decrease their effectiveness very significantly: the antiviral immune response causes the elimination of the therapeutic effect, and the poor natural ability of oncolytic viruses to infect micrometastatic lesions significantly minimizes the effective dose of virus. This review will focus on updating the technical and scientific foundations of one of the strategies developed to overcome these limitations, ie, using cells as vehicles for oncolytic viruses. Among many candidates, a special type of adult stem cell, mesenchymal stem cells (MSCs), have already been used in the clinic as cell vehicles for oncolytic viruses, partly due to the fact that these cells are actively being evaluated for other indications. MSC carrier cells are used as Trojan horses loaded with oncoviruses, are administered systemically, and release their cargos at the right places. MSCs are equipped with an array of molecules involved in cell arrest in the capillaries (integrins and selectins), migration toward specific parenchymal locations within tissues (chemokine receptors), and invasion and degradation of the extracellular matrix (proteases). In addition to anatomical targeting capacity, MSCs have a well-recognized role in modulating immune responses by affecting cells of the innate (antigen-presenting cells, natural killer cells) and adaptive immune system (effector and regulatory lymphocytes). Therefore, carrier MSCs may also modulate the immune responses taking place after therapy, ie, the antiviral and the antitumor immune responses.

RETRACTED: The Oncolytic Virus in Cancer Diagnosis and Treatment

“…Carrier cell research is moving toward using cells that not only provide shielding from antibodies and complement but also detarget from off-target organs, home to tumor sites, and exert their antitumor effector functions. At present, the most commonly used cell carriers are cell carriers including antigen-specific T cell (AST), cytokine-induced killer cell (CIK), mesenchymal stem cells, and blood outgrowth endothelial cells (BOECs) ( 97 – 99 ). An optimal cell carrier must include the following characteristics: first, it must be susceptible to virus’ infection; second, it can assist the virus in locating the tumor tissue while not being recognized by the immune system; finally, it has the ability to release progeny virus to attack distant cancer cells ( 100 ).…”

Cellular Virotherapy Increases Tumor-Infiltrating Lymphocytes (TIL) and Decreases their PD-1+ Subsets in Mouse Immunocompetent Models

“…In this way, this cellular virotherapy can be administered in cases in which the tumor is not accessible and may even act in tumors or metastases that have not been found. Furthermore, this “Trojan horse” strategy may also evade the initial immune response of the patient against the viral presence and protect the oncolytic virus when it is transported inside the cell [ 6 ]. In fact, different studies suggest that antitumor efficacy of oncolytic adenovirus (OAd) carried by MSCs may even improve the antitumor effect triggered by OAd alone, while treatment with MSCs alone did not induce any antitumor effect [ 7 , 8 , 9 ].…”

p19Arf sensitizes B16 melanoma cells to interferon-β delivered via mesenchymal stem cells in vitro

“…For the latter, autologous MSCs may be isolated from the circulation, bone marrow, or adipose tissue, including lipoaspirates, cultivated in the laboratory, modified and expanded ex vivo, and then infused in the patient (4)(5)(6). The use of MSCs as a delivery vehicle for the therapeutic payload has been shown to home to and infiltrate the tumor site where they provide therapeutic transgene levels while shielding the gene transfer vector from immune recognition (7)(8)(9)(10)(11).…”