Survey
Directing systemic oncolytic viral delivery to tumors via carrier cells

https://doi.org/10.1016/j.cytogfr.2010.02.004Get rights and content

Abstract

The systemic administration of oncolytic virus (OV) is often inefficient due to clearance of the virus by host defense mechanism and spurious targeting of non-cancer tissues through the bloodstream. Cell mediated OV delivery could hide the virus from host defenses and direct them toward tumors: Mesencymal and neural stem cells have been described to possess tumor-homing ability as well as the capacity to deliver OVs. In this review, we will focus on approaches where OV and carrier cells are utilized for cancer therapy. Effective cellular internalization and replication of OVs need to occur both in cancer and carrier cells. We thus will discuss the current challenges faced by the use of OV delivery 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

References (70)

  • M. Studeny et al.

    Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors

    Cancer Res

    (2002)
  • T. Hakkarainen et al.

    Human mesenchymal stem cells lack tumor tropism but enhance the antitumor activity of oncolytic adenoviruses in orthotopic lung and breast tumors

    Hum Gene Ther

    (2007)
  • R.L. Yong et al.

    Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas

    Cancer Res

    (2009)
  • J. Qiao et al.

    Purging metastases in lymphoid organs using a combination of antigen-nonspecific adoptive T cell therapy, oncolytic virotherapy and immunotherapy

    Nat Med

    (2008)
  • K.W. Culver et al.

    In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors

    Science

    (1992)
  • S. Benedetti et al.

    Gene therapy of experimental brain tumors using neural progenitor cells

    Nat Med

    (2000)
  • G. Coukos et al.

    Use of carrier cells to deliver a replication-selective herpes simplex virus-1 mutant for the intraperitoneal therapy of epithelial ovarian cancer

    Clin Cancer Res

    (1999)
  • D.H. Lee et al.

    Targeting rat brainstem glioma using human neural stem cells and human mesenchymal stem cells

    Clin Cancer Res

    (2009)
  • R.O. Oreffo et al.

    Mesenchymal stem cells: lineage, plasticity, and skeletal therapeutic potential

    Stem Cell Rev

    (2005)
  • B.M. Abdallah et al.

    The use of mesenchymal (skeletal) stem cells for treatment of degenerative diseases: current status and future perspectives

    J Cell Physiol

    (2009)
  • E. Spaeth et al.

    Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells

    Gene Ther

    (2008)
  • R.K. Jain et al.

    Angiogenesis in brain tumours

    Nat Rev Neurosci

    (2007)
  • C. Fehrer et al.

    Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan

    Aging Cell

    (2007)
  • F. Djouad et al.

    Earlier onset of syngeneic tumors in the presence of mesenchymal stem cells

    Transplantation

    (2006)
  • M.A. Stoff-Khalili et al.

    Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma

    Breast Cancer Res Treat

    (2007)
  • A.M. Sonabend et al.

    Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma

    Stem Cells

    (2008)
  • S. Komarova et al.

    Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses

    Mol Cancer Ther

    (2006)
  • D.T. Josiah et al.

    Adipose-derived stem cells as therapeutic delivery vehicles of an oncolytic virus for glioblastoma

    Mol Ther

    (2009)
  • G. Lazennec et al.

    Concise review: adult multipotent stromal cells and cancer: risk or benefit?

    Stem Cells

    (2008)
  • N.G. Rainov et al.

    Selective uptake of viral and monocrystalline particles delivered intra-arterially to experimental brain neoplasms

    Hum Gene Ther

    (1995)
  • K. Ikeda et al.

    Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses

    Nat Med

    (1999)
  • D. Schellingerhout et al.

    Quantitation of HSV mass distribution in a rodent brain tumor model

    Gene Ther

    (2000)
  • F.H. Gage

    Mammalian neural stem cells

    Science

    (2000)
  • K. Ohira et al.

    Ischemia-induced neurogenesis of neocortical layer 1 progenitor cells

    Nat Neurosci

    (2009)
  • K.S. Aboody et al.

    Stem and progenitor cell-mediated tumor selective gene therapy

    Gene Ther

    (2008)
  • Cited by (59)

    • 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 Oncolytics
      Citation 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 Reviews
      Citation 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].

    • Oncolytic viruses as a promising therapeutic strategy for hematological malignancies

      2021, Biomedicine and Pharmacotherapy
      Citation 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].

    View all citing articles on Scopus

    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.

    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.

    View full text