SurveyDirecting systemic oncolytic viral delivery to tumors via carrier cells☆
Introduction
Although the majority of applications of gene therapy for human diseases have relied upon direct administration into the target tissue, systemic administration is generally thought to be more reliable, easy, and more appealing, particularly for diseases that affect multiple tissues. This is especially true for cancers. However, when one considers systemic routes with gene therapy vectors, multiple challenges exist, related to tropism/targeting and effects of the circulating humoral and cellular host defenses against such vectors. One exciting avenue that has been exploited by multiple groups recently has employed mammalian cells as a carrier for gene therapy vectors [1], [2], [3]. Such carrier cells possess the advantage of hiding the vector from circulating humoral and cellular defense mediators, and, in some cases, have been shown to be targetable to the tissue of interest, particularly in the case of tumors [4], [5], [6]. In this chapter, we plan to review the current state of the art in cell-mediated delivery of such vectors to tumors, especially focusing on adenovirus and herpes simplex virus type 1 (HSV-1), where mesenchymal and neural stem cells have been engineered to act as carriers.
Section snippets
Carrier cell types
The innate and adaptive immune system can be an efficient host defense, largely responsible for eliminating circulating naked virions before they reach a tumor. It is widely accepted that a more efficient delivery system for naked virions is needed to improve their therapeutic efficacy, especially against metastatic or diffusely infiltrating tumors. Attempts to use cells to deliver anti-cancer agents date back nearly two decades [7]. Autologous host mammalian cells would not be recognized as
Improving the transduction of carrier cells
The process of loading carrier cells with OVs or gene therapy vectors has received relatively limited attention. Efficiency in this process would greatly improve the development of large preclinical and clinical batches of such cells for trials in humans. In this section, we will focus on the areas where such efficiency has been investigated.
Extending the life span of virus-loaded carrier cells
Although oncolytic viruses are attenuated by a variety of stratagems to restrict replication in normal tissues, most cells utilized as carriers are relatively permissive for viral replication, partly due to the fact that they self-renew and cycle (MSCs and NSCs). Therefore, the survival time of a virus-loaded carrier cell is limited [2], [18], [20]. It is difficult to reliably regulate viral replication in the carrier cells so that timely release of the OV load occurs in the tumor, rather than
Conclusion
Carrier cell-based delivery of OVs and genes requires the integration of multiple types of expertise, from viral design to carrier cell preparation, from kinetics of cell and viral life cycles to pharmacokinetics. Future efforts in improving all of these research areas may lead to efficient clinical applications of this technology.
Hiroshi Nakashima received his PhD degree at Osaka University Graduate School of Medicine in Japan in 2005. From 2001 to 2004 he was also a pre-doctoral research fellow in the Japan Society for the Promotion of Science and a visiting graduate student at Nagoya University in Japan, researching mammalian chromosome organization and chromatin structures using human artificial chromosome technology. In 2006, he started as a postdoctoral researcher in Dr. Chiocca's Dardinger laboratory, in the
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Enhanced tumor targeting and timely viral release of mesenchymal stem cells/oncolytic virus complex due to GRP78 and inducible E1B55K expressions greatly increase the antitumor effect of systemic treatment
2022, Molecular Therapy OncolyticsCitation Excerpt :Mesenchymal stem cells (MSCs) are attractive candidates for delivery to tumor sites due to low immunogenicity and a tendency to migrate toward tumors; in addition, MSCs are technically simple to obtain and are associated with minimal ethical complications.10,11 MSC-mediated oncolytic virus delivery may shield the virus from host defenses in transit.8,10,12 However, few studies have investigated the therapeutic use of MSCs for systemic oncolytic virus administration, which may be due to poor tumor homing, inadequate oncolytic virus production or release, and the possible risk of MSC oncogenic potential after extended passage in culture.
Mesenchymal stem cells: A living carrier for active tumor-targeted delivery
2022, Advanced Drug Delivery ReviewsCitation Excerpt :In addition, similar to the amplification effect of suicide gene therapy, the destroyed tumor cells release new infectious virus particles and stimulate the antitumor immune response to destroy the uninfected tumor cells [290]. Nevertheless, the efficiency of this therapeutic strategy is highly hindered by the delivery approach, due to clearance of the viruses by the host immune system, as well as the off-targeting of tumor cells [293]. Therefore, incorporating oncolytic viruses in MSCs to avoid the immune recognition for efficient tumor-targeted delivery is an attractive option [294].
Development of oncolytic viruses for cancer therapy
2021, Translational ResearchOncolytic viruses as a promising therapeutic strategy for hematological malignancies
2021, Biomedicine and PharmacotherapyCitation Excerpt :Stem/progenitor cells, immune cells and transformed cells are the three major types of cells used as viral vectors. With acknowledged tumor-homing properties [44], stem cells from various sources, such as adipose-derived stem cells (ADSCs), neural stem cells (NSCs),and mesenchymal stem cells (MSCs) have been used as carriers of OVs to treat tumors [45]. Surprisingly, the ability of MSCs to protect oncolytic MVs from humoral immunity was reported in an acute lymphoblastic leukemia (ALL) model [46].
Retargeted and Multi-cytokine-Armed Herpes Virus Is a Potent Cancer Endovaccine for Local and Systemic Anti-tumor Treatment
2020, Molecular Therapy OncolyticsMyxoma Virus-Loaded Mesenchymal Stem Cells in Experimental Oncolytic Therapy of Murine Pulmonary Melanoma
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Hiroshi Nakashima received his PhD degree at Osaka University Graduate School of Medicine in Japan in 2005. From 2001 to 2004 he was also a pre-doctoral research fellow in the Japan Society for the Promotion of Science and a visiting graduate student at Nagoya University in Japan, researching mammalian chromosome organization and chromatin structures using human artificial chromosome technology. In 2006, he started as a postdoctoral researcher in Dr. Chiocca's Dardinger laboratory, in the Department of Neurological Surgery at James Comprehensive Cancer Center and The Ohio State University Medical Center. He was a recipient of the 2007 travel award at the American Society of Gene Therapy. He has been working on the development of brain cancer gene therapy using stem cell carriers and oncolytic viruses.
Dr. Balveen Kaur majored in physics at Delhi University and proceeded to obtain an MS in biotechnology at Banaras Hindu University. She subsequently carried out her PhD at Emory University, followed by a postdoctoral fellowship in the laboratory of Dr. Erwin Van Meir at Emory University where she studied the role of angiogenesis in the context of glioma progression. Much of her work focused on the tumor microenvironment and the antiangiogenic and antitumorigenic properties of endogenous inhibitors. She joined the faculty of The Ohio State University in 2005 where she is currently Associate Professor, where her laboratory is currently studying the role of the tumor microenvironment and angiogenesis as limiting factors for glioma virotherapy.
E. Antonio Chiocca, MD, PhD has been the chair of the Ohio State University Medical Center Department of Neurological Surgery since 2004. He holds the Dardinger Family Endowed Chair in Oncological Neurosurgery at the James Comprehensive Cancer Center. He was previously an associate professor of Neurosurgery at Massachusetts General Hospital/Harvard Medical School (MGH/Harvard), where he also completed his residency. He obtained his MD/PhD from the University of Texas Medical School in Houston in 1988. He has published more than 220 papers and chapters related to glioma biology and treatment. He has held continuous NIH funding since 1995 and has also been funded by numerous private foundations for his research on gliomas. He was awarded the Grass Foundation Award by the Society for Neurological Surgery in 2007 and the Farber Award for Brain Tumor Research by the Society for Neuro-oncology in 2008. He was elected to the American Society for Clinical Investigation (ASCI) in 2005 and as a fellow of the American Association for the Advancement of Sciences (AAAS) in 2005. He has been a member of the National Cancer Institute (NCI) – D (clinical studies) parent committee and of NCI's Developmental Therapeutics Study Section. He also sits on the scientific advisory board for the American Brain Tumor Association, the Goldhirsh Foundation and the Sonntag foundation. He sits on the editorial board of several journals, including Molecular Therapy, Journal of Neurosurgery and Neurosurgery. His research has focused on developing novel treatments for brain tumors, including gene-based and virus-based therapies. He has also worked on mechanistic aspects of brain tumor biology.
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This work was supported by funding from the National Institutes of Health Grant K01NS059575; R01NS064607; R21NS056203 to BK, and R21NS0632901; U01 NS061811; P01 CA069246 to EAC.