سلولهای بنیادی مزانشیمی به عنوان حامل تحویل سیستمیک ویروسهای انکولیتیک
Abstract
1- Introduction
2- Mesenchymal stem cells: an overview
3- Engineered MSCs
4- Engineered oncolytic viruses
5- Immune checkpoint inhibitors and oncolytic therapy
6- Non-systemic anticancer therapy with oncolytic virus-loaded MSCs
7- Systemic anticancer therapy with oncolytic virus-loaded MSCs
8- Limitations of MSC use in systemic therapy
9- MSC-mediated oncolytic virotherapy - clinical studies
10- Future directions
References
Abstract
Progress in genetic engineering led to the emergence of some viruses as potent anticancer therapeutics. These oncolytic viruses combine self-amplification with dual antitumor action: oncolytic (destruction of cancer cells) and immunostimulatory (eliciting acquired antitumor response against cancer epitopes). As any other viruses, they trigger antiviral response upon systemic administration. Mesenchymal stem cells are immature cells capable of self-renewing and differentiating into many cell types that belong to three germinal layers. Due to their inherent tumor tropism mesenchymal stem cells loaded with oncolytic virus can improve delivery of the therapeutic cargo to cancer sites. Shielding of oncolytic viral construct from antiviral host immune response makes these cells prospective delivery vehicles to even hard-to-reach metastatic neoplastic foci. Use of mesenchymal stem cells has been criticized by some investigators as limiting proliferative abilities of primary cells and increasing the risk of malignant transformation, as well as attenuating therapeutic responses. However, majority of preclinical studies indicate safety and efficacy of mesenchymal stem cells used as carriers of oncolytic viruses. In view of contradictory postulates, the debate continues. The review discusses mesenchymal stem cells as carriers for delivery of genetically engineered oncolytic constructs and focuses on systemic approach to oncoviral treatment of some deadly neoplasms.
Introduction
Despite unquestionable progress in cancer treatment, several malignancies still tend to elude successful cure or medically-induced remission. Continued rise in morbidity in the last twenty years for gliomas, melanoma or pancreatic cancer makes them a major public health concern and a research challenge. Although radically improved outcomes might be unattainable yet, stepwise progress is likely with novel or improved treatments involving immunotherapy, cell-based therapeutics, oncolytic virotherapy and hybrid approaches. Intriguing recoveries from cancer following natural viral infection (e.g. measles) have been known to medicine since early 20th century but this early lead based on use of wild-type adenovirus, poliovirus or Coxsackie virus was marred by virus-associated morbidity and complications and was later abandoned (Kelly et al., 2007). Clinical utility of oncolytic viruses has been steadily regaining ground since the latter part of the 20th century with advances in genetic engineering. Current generation of many oncolytic viral constructs allows targeting and destroying cancer cells while toxicities to surrounding normal tissues are minimized. A concurrent development in cell-based anticancer therapies has led to the concept of oncoviral viruses’ delivery to tumors via cellular carriers. It assumes that certain types of cells pre-loaded ex vivo with some curative cargo can be administered systemically, delivered to and released in target tissues.