Don’t let the fancy name scare you off. The underlying concepts are fairly simple. The basic idea is to go after cancer cells with viruses that kill them. To help the viruses escape the immune system, they are packaged in stem cells that are expected to snuggle up to the cancer cells. It is hoped that the approach will go after cancer stem cells as well as mature cancer cells and therefore possibly provide a basic cure for the cancer concerned. The broader area, oncolytic virotherapy is an approach to curing cancers that has been intensely researched for a number of years. What is new is using stem cells or other human cells for safely getting the viruses to and into the target cancer cells.
The 10th theory of aging in my treatise is Susceptibility to Cancers. The probability of incidences of cancer rises rapidly with advanced aging. Cancer is second major cause of age-associated mortality and cancer in turn often induces other age-related maladies. Finally, cancer therapies like radiation and some forms of chemotherapy can accelerate the aging process. The War on Cancer going back to 1971 has produced marginal results for the hundreds of billions of dollars spent on research. In 2008 the NCI spent $4.83 billion on 5,380 research grants. The relative lack of progress for the amount of effort invested is probably due to the fact that basic scientific knowledge related to the biomolecular, cell-cycle, signaling pathways, genetic and epigenetic processes involved in cancer did not exist until recent years. And this knowledge could not exist until extremely powerful computers capable of analyzing molecular, genomic and proteomic data became available. So, the early approaches to curing cancer tended to be trial-and-error approaches based on screening chemical compounds which mostly ended in failure. Many current approaches are much more sophisticated, however, and stem cell oncolytic virotherapy is one of them.
On oncolytic virotherapy
The idea of plain-old oncolytic virotherapy is more than 50 years old though most real progress has been made in the last dozen years. See the 2007 publication Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress. “Therapeutic oncolytic viruses (virotherapeutics) constitute a novel class of targeted anticancer agents that have unique mechanisms of action compared with other cancer therapeutics. The development of virotherapeutics has evolved from the use of in vitro-passaged strains (first generation), to genetically engineered selectivity-enhanced viruses (second generation) and finally to genetically engineered transgene-expressing ‘armed’ oncolytic viruses (third generation). Descriptions of cancer remissions following virus infections date back to a century ago. Initial patient treatment publications, written up to 50 years ago, consisted of case reports or case series of treatment with first-generation, non-engineered viruses. Over the past decade, hundreds of patients with cancer have been treated on prospectively designed clinical trials (including phase III), evaluating over 10 different agents, including engineered second-generation and third-generation viruses. This Review summarizes and interprets the data from clinical reports over the last century, including safety, efficacy and biological end points (viral and immunologic).”
By 2008 much progress had been made as indicated in the publication Oncolytic virotherapy: molecular targets in tumor-selective replication and carrier cell-mediated delivery of oncolytic viruses. “Tremendous advances have been made in developing oncolytic viruses (OVs) in the last few years. By taking advantage of current knowledge in cancer biology and virology, specific OVs have been genetically engineered to target specific molecules or signal transduction pathways in cancer cells in order to achieve efficient and selective replication. The viral infection and amplification eventually induce cancer cells into cell death pathways and elicit host antitumor immune responses to further help eliminate cancer cells. Specifically targeted molecules or signaling pathways (such as RB/E2F/p16, p53, IFN, PKR, EGFR, Ras, Wnt, anti-apoptosis or hypoxia) in cancer cells or tumor microenvironment have been studied and dissected with a variety of OVs such as adenovirus, herpes simplex virus, poxvirus, vesicular stomatitis virus, measles virus, Newcastle disease virus, influenza virus and reovirus, setting the molecular basis for further improvements in the near future. Another exciting new area of research has been the harnessing of naturally tumor-homing cells as carrier cells (or cellular vehicles) to deliver OVs to tumors. The trafficking of these tumor-homing cells (stem cells, immune cells and cancer cells), which support proliferation of the viruses, is mediated by specific chemokines and cell adhesion molecules and we are just beginning to understand the roles of these molecules.”
So, with all that great history and the discovery of many powerful anti-cancer viruses, why are oncolytic virotherapies not now in widespread use? A large part of the answer appears to be that usually a) there is a problem getting the virus specifically to the cancer cells and b) the human immune system detects and wipes out the virus before it can get to the cancer cells and do its job. The immune system in such a case is just doing its job. The 2008 publication Cell carriers to deliver oncolytic viruses to sites of myeloma tumor growth reports “Several studies have illustrated the potential of utilizing oncolytic viruses (measles, vaccinia, Vesicular Stomatitis Virus and coxsackievirus A21) for the treatment of MM (multiple myeloma), but there are significant barriers that prevent the viruses from reaching sites of myeloma tumor growth after intravenous delivery. The most important barriers are failure to extravasate from tumor blood vessels, mislocalization of the viruses in liver and spleen and neutralization by antiviral antibodies.” These problems have led to approaches using “Trojan horse” cells that hide the viruses from the immune system and that can home-in to the cancer cells.
Cell-based oncolytic virotherapy
The March 2010 publication Crossing the boundaries: stem cells and gene therapy provides an overview of the current situation. “Oncolytic virotherapy is an emerging therapeutic modality for the treatment of cancer. It entails construction of viruses with the ability to selectively target and lyse tumor cells. This branch of therapy has significantly advanced in the past decade, heralded by the development of several novel viruses. Despite the initial success of oncolytic virotherapy in the preclinical setting, however, this treatment modality remains hindered by several obstacles. First, failure to achieve effective viral delivery to targeted tumor beds is a well known limitation. Second, the virus-neutralizing mechanisms of the host immune system, which are in place to protect from viral pathogens, may also hinder the therapeutic potential of virotherapy. One approach to tackling these shortcomings is the use of cell-based carriers to both help with delivery of the virus and shield it from immunosurveillance. Stem cells have recently surfaced as a potential cell-based candidate for delivery of virotherapy. Their unique migratory and immunosuppressive qualities have made them an exciting area of investigation. The focus of this review is to discuss the benefits of stem-cell-based delivery of oncolytic virotherapy and its role in cancer treatment.”
The idea of using cells to deliver oncolytic viruses in cells goes back a few years. The 2007 publication Cell-based delivery of oncolytic viruses: a new strategic alliance for a biological strike against cancer outlined the strategy of cell-based delivery but at that time did not emphasize the use of stem cells as delivery vehicles. The 2009 report Cell carriers for oncolytic viruses: Fed Ex for cancer therapy amplifies on this theme. “Oncolytic viruses delivered directly into the circulation face many hazards that impede their localization to, and infection of, metastatic tumors. Such barriers to systemic delivery could be overcome if couriers, which confer both protection, and tumor localization, to their viral cargoes, could be found. Several preclincal studies have shown that viruses can be loaded into, or onto, different types of cells without losing the biological activity of either virus or cell carrier. Importantly, such loading can significantly protect the viruses from immune-mediated virus-neutralizing activities, including antiviral antibody. Moreover, an impressive portfolio of cellular vehicles, which have some degree of tropism for tumor cells themselves, or for the biological properties associated with the tumor stroma, is already available.”
Stem cells appear to be excellent candidates for the Trojan horse role.
The 2010 publication Treatment of metastatic neuroblastoma with systemic oncolytic virotherapy delivered by autologous mesenchymal stem cells: an exploratory study reports on a small-scale human trial: “The tumor stroma engrafting property of intravenously injected mesenchymal stem cells (MSCs) may allow the use of MSCs as cellular vehicles for targeted delivery. In this work, we study the safety and the efficacy of infusing autologous MSCs infected with ICOVIR-5, a new oncolytic adenovirus, for treating metastatic neuroblastoma. Four children with metastatic neuroblastoma refractory to front-line therapies received several doses of autologous MSCs carrying ICOVIR-5, under an approved preliminary study. The tolerance to the treatment was excellent. A complete clinical response was documented in one case, and the child is in complete remission 3 years after this therapy. We postulate that MSCs can deliver oncolytic adenoviruses to metastatic tumors with very low systemic toxicity and with beneficial antitumor effects.”
A May 2009 blog entry Trojan-horse stem cells might offer an important new cancer therapy discusses an approach to killing cancer stem cells that is very akin to the one described here. Instead of the death payload delivered to cancer cells being an oncolytic adenovirus as discussed here, the payload in the case of that blog entry is a molecule called TRAIL (A TNF-related apoptosis-inducing ligand in case you wanted to know). “TRAIL induces apoptosis via death receptors (DR4 and DR5) in a wide variety of tumor cells but not in normal cells(ref).”
Lots of research action
There is much more going on relating to oncolytic virotherapy, way more than I can start to cover here. Here, for example, is a starting list of relevant publications produced in 2010 alone:
· A High-throughput Pharmacoviral Approach Identifies Novel Oncolytic Virus Sensitizers.
· Regression of human prostate tumors and metastases in nude mice following treatment with the recombinant oncolytic vaccinia virus GLV-1h68.
· Oncolytic measles viruses encoding interferon beta and the thyroidal sodium iodide symporter gene for mesothelioma virotherapy.
· Oncolytic herpes simplex virus vectors and chemotherapy: are combinatorial strategies more effective for cancer?
· Adenovirus retargeting to surface expressed antigens on oral mucosa.
· Antiangiogenic cancer therapy combined with oncolytic virotherapy leads to regression of established tumors in mice.
· Crossing the boundaries: stem cells and gene therapy.
· Regression of advanced rat and human gliomas by local or systemic treatment with oncolytic parvovirus H-1 in rat models.
· Cancer Stem Cells: The Final Frontier for Glioma Virotherapy.
· Noninvasive monitoring of mRFP1- and mCherry-labeled oncolytic adenoviruses in an orthotopic breast cancer model by spectral imaging.
· United virus: The oncolytic tag-team against cancer!
· Combining oncolytic virotherapy and tumour vaccination.
· Clinical trials with oncolytic reovirus: Moving beyond phase I into combinations with standard therapeutics.
· Oncolytic herpes simplex virus armed with xenogeneic homologue of prostatic acid phosphatase enhances antitumor efficacy in prostate cancer.
· Oncolytic parvoviruses as cancer therapeutics.
· Evaluation of continuous low dose rate versus acute single high dose rate radiation combined with oncolytic viral therapy for prostate
Treatment of metastatic neuroblastoma with systemic oncolytic virotherapy delivered by autologous mesenchymal stem cells: an exploratory study.
· Double-regulated oncolytic adenovirus-mediated IL-24 overexpression exhibits potent antitumor activity on gastric adenocarcinoma.
· Oncolysis using herpes simplex virus type 1 engineered to express cytosine deaminase and a fusogenic glycoprotein for head and neck squamous cell carcinoma.
· Type I interferon-sensitive recombinant newcastle disease virus for oncolytic virotherapy.
· Oncolysis of prostate cancers induced by vesicular stomatitis virus in PTEN knockout mice.
· Oncolytic (replication-competent) adenoviruses as anticancer agents.
· Combination gene therapy of lung cancer with conditionally replicating adenovirus and adenovirus-herpes simplex virus thymidine kinase.
· Phase I trial of intraperitoneal administration of an oncolytic measles virus strain engineered to express carcinoembryonic antigen for recurrent ovarian cancer.
· Parvovirus H1 selectively induces cytotoxic effects on human neuroblastoma cells.
· Potent anti-tumor effects of a dual specific oncolytic adenovirus expressing apoptin in vitro and in vivo.
· Vesicular stomatitis virus oncolysis is potentiated by impairing mTORC1-dependent type I IFN production.
· Myxoma virus virotherapy for glioma in immunocompetent animal models: optimizing administration routes and synergy with rapamycin.
· Improved potency and selectivity of an oncolytic E1ACR2 and E1B19K deleted adenoviral mutant in prostate and pancreatic cancers.
· hTERT-promoter-dependent oncolytic adenovirus enhances the transduction and therapeutic efficacy of replication-defective adenovirus vectors in pancreatic cancer cells.
· Antitumor effects of telomelysin in combination with paclitaxel or cisplatin on head and neck squamous cell carcinoma.
· Intelligent design: combination therapy with oncolytic viruses.
· International Society for Cell and Gene Therapy of Cancer 2009 Annual Meeting held in Cork, Ireland.
· Single-cycle viral gene expression, rather than progressive replication and oncolysis, is required for VSV therapy of B16 melanoma.
· Multimodal approach using oncolytic adenovirus, cetuximab, chemotherapy and radiotherapy in HNSCC low passage tumour cell cultures.
· Adenovirus-mediated cancer gene therapy and virotherapy (Review).
Despite all this history, the use of stem cells as delivery vectors for oncolytic viruses is fairly new and this aspect of oncolytic virotherapy is still largely in the preclinical stage.
The bottom line?
Do I think cell-delivered oncolytic virotherapy will be an effective approach to wiping out cancers? My guess is that the answer depends on whether the particular virotherapy concerned infects and wipes out cancer stem cells as well as cancer cells. If the answer is “no” then the cell-delivered oncolytic virotherapy will be just another in a long list of ways to send the cancer into temporary remission with a high probability of it returning. Paying lots of attention to the virus delivery vehicle and little attention to whether the delivered virus will wipe out cancer stem cells is not likely to get us very far.
The 2008 publication Virotherapy as An Approach Against Cancer Stem Cells is optimistic in this respect. “Targeting of cancer stem cells might be key for improving survival and producing cures in patients with metastatic tumors. Viruses enter cells though infection and might therefore not be sensitive to stem cell resistance mechanisms. During the last decades, oncolytic adenoviruses have been shown to effectively kill cancer cells, by seizing control of their DNA replication machinery and utilizing it for the production of new virions, ultimately resulting in the rupture of the cell.” The 2007 publication Targeting the Untargetable: Oncolytic Virotherapy for the Cancer Stem Cell appears also to be tentatively optimistic. “Oncolytic viruses may represent an effective therapeutic approach to target cancer stem cells.6,7 ”
If the authors are right and the virotherapy kills cancer stem cells, then at last we might be on the way to real cancer cures. Finally!
Have you ever considered creating an e-book or guest authoring on other sites? I have a blog based on the same theme if you’re interested.