Journal of the National Cancer Institute Advance Access originally published online on September 23, 2008
JNCI Journal of the National Cancer Institute 2008 100(19):1350-1351; doi:10.1093/jnci/djn356
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© Oxford University Press 2008.
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Cancer-killing Viruses Assist Gene Therapies
In the beginning of the last century, scientists were surprised to discover that cancer patients infected with a viral illness sometimes experienced tumor regressions, as did patients given attenuated viral vaccines. By the end of the century, researchers performing early gene therapy experiments were using viruses as delivery vehicles, or vectors, to insert genes into cells, taking advantage of the viruses’ innate ability to infect cells, replicate, cause cell death, release viral particles, and spread.
"In the first human gene therapy trials in the 1990s, only nonreplicating viruses were used as vectors because of safety concerns," said Evanthia Galanis, M.D., professor of oncology at the Mayo Clinic in Rochester, Minn. "This taught us an important lesson: Using nonreplicating viruses resulted in infection or therapeutic gene expression in only a small percentage of tumor cells.
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"Modifying viruses in a smart way to enable them to replicate and be as cancer specific as possible, while sparing normal cells, was the next step," Galanis said. Because of these early trials, oncolytic, or cancer-killing, tumor viruses are now one of the most active areas of gene therapy research in cancer, with several proof-of-principle studies ongoing.
"Viruses can be reprogrammed into oncolytic vectors by combining three types of modification: targeting, arming, and shielding," said Michael Barry, Ph.D., professor of medicine at the Mayo Clinic. The idea is that a virus that can replicate only in cancer cells will multiply within the cells and kill them, releasing new copies of the virus to surrounding cells when they die, thereby infecting other tumor cells locally and at distant sites.
Viruses used for oncolytic cancer therapy include adenoviruses, vaccinia, herpes simplex type 1, Newcastle disease virus, measles, retroviruses, vesicular stomatitis virus, and reoviruses.
Early Steps
Early oncolytic viral therapy focused on intratumoral injection, Galanis said. "This was an important early step for cancer virotherapy, in order to establish the safety first in human administration," she said. But cancer is a systemic disease for most patients, and intratumoral administration of viruses is practical only for certain tumor types that tend to recur locally, such as head and neck cancers or gliomas.
So researchers tried next to determine how best to give oncolytic viruses intravenously. The challenges are twofold: to direct viruses to the tumor environment and to find ways to bypass the immune system. Several approaches are being tested in preclinical studies, and some of them are currently being evaluated in clinical trials, Galanis said. These efforts include limiting treatments to patients who don’t have an immune response to a particular virus, combining viruses with immunosuppressive drugs, and using a patient's own cells as carriers to bypass the antiviral immune response and deliver the viruses more effectively. "Using a patient's peripheral blood monocyte cells is one good option because they gravitate to tumors and bypass the immune response problem," Galanis said. Another approach is to create coatings for the viruses that will not be recognized by the patient's immune system.
Overall, researchers are aiming to make viruses used in oncolytic gene therapy as tumor specific as possible, Galanis said. For glioma therapy, she is targeting oncolytic measles strains by using an antibody against EGFRvIII, a glioma-specific receptor, or by displaying interleukin 13, which recognizes the interleukin 13 Ra2 receptor, also overexpressed in high-grade gliomas.
Clinical Trials Moving Forward
Several oncolytic viruses are in early-stage testing as monotherapies, as well as in combination with chemotherapy and radiation. Older gene therapy companies such as Introgen and Cell Genesys of South San Francisco, Calif., have added oncolytic viruses to their portfolios, and a growing number of new companies, including BioVex of Woburn, Mass., Jennerex in San Francisco, and Oncolytics in Calgary, Canada, are developing genetic therapies using oncolytic viruses.
Jennerex chose to modify a vaccinia virus rather than use an adenovirus—the common cold virus, which proved to be less potent than expected—because vaccinia is inherently oncolytic and can be delivered intravenously to metastatic cancers. The vaccinia virus is from the same poxvirus family as the cowpox virus used by British physician Edward Jenner to make the world's first vaccine against smallpox in 1796. Jennerex founder and CEO David Kirn, M.D., and collaborator John Bell, Ph.D., of the Ottawa Health Research Institute in Canada are also developing and optimizing products from the rhabdovirus family. This family of viruses induces immune responses that lead to the viruses’ being shut down in normal tissues, though they remain oncolytic in cancer cells. These two classes of viruses destroy tumors by multiple mechanisms, including viral lysis (destruction of cells by the viruses), tumor vascular shutdown, and induction of a systemic immune response to cancer.
"Early on..., we didn’t realize that efficient virus spread in cancer cell cultures would not necessarily be predictive of results in solid tumors in humans. A better virus biology was needed," Kirn said. By deleting the thymidine kinase gene from its vaccinia gene therapy, JX-594, Jennerex improved the treatment's selectivity for cancer by limiting replication to cancer cells but not in normal cells. Jennerex also armed JX-594 with the granulocyte-macrophage colony-stimulating factor gene to stimulate a systemic antitumor immune response.
Results of a phase I/II trial testing with JX-594, Jennerex’ most clinically advanced therapy, were published in May in The Lancet Oncology. Investigators reported that most of 14 treated patients with end-stage cancer within the liver (primary liver cancer or metastases) experienced replication and systemic intravenous spread of the virus, followed by tumor destruction. Patients who received intratumoral injections tolerated the drug well, with liver and lung cancer patients benefiting the most.
BioVex reported results from a phase II trial with OncoVEX, a herpes simplex virus modified to contain the granulocyte-macrophage colony-stimulating factor gene, at the annual meeting of the American Society of Clinical Oncology. Forty-three advanced metastatic melanoma patients were given OncoVEX intratumorally every 2 weeks for up to a year. More than a quarter of the patients in the trial had tumor shrinkage, whereas others showed periods of stable disease or posttreatment responses after being withdrawn from the study because of initial progression. Six patients had complete responses—five of which are ongoing at 4–27 months after the first injection. Another six had partial responses—five of which are ongoing 7–13 months after the first injection, with two of those patients having no disease after surgery to remove residual tumors. Of the original 14 patients, half remain in the study with stable disease 3–10 months after beginning therapy. The side effects were mild—mostly transient, flulike symptoms. A phase III trial in previously treated melanoma patients is slated to begin in early 2009.
Oncolytics Biotech may be conducting the most oncolytic gene therapy trials, with 10 phase I/II and II trials in the U.S. and the UK. They are testing Reolysin, an unmodified human reovirus, in a range of solid tumors and metastatic cancer as a monotherapy and in combination with chemotherapy and radiation, with local or systemic delivery. Reolysin is a nonpathogenic virus that replicates only in cells with an activated Ras pathway, characteristic of about 75% of cancers.
The company recently discovered that viral oncolysis triggers the production of tumor antigens, which in turn primes the immune system to recognize and kill tumor cells. It also found that adoptive cell transfer with activated T cells can improve and mitigate the immune system's efforts to deactivate the virus.
One flaw of oncolytic viral gene therapy, however, is that it increases vascular permeability, inflammatory gene expression, and leukocyte infiltration—a perfect recipe for angiogenesis and tumor growth, according to Balveen Kaur, Ph.D., of Ohio State University in Columbus. But administering one dose of an antiangiogenic peptide before treatment counteracts angiogenesis and enhances the virus’ efficacy, Kaur said.
The field is still grasping for the best approach, but experts say that oncolytic viruses could play an important role in gene therapy for cancer. "Oncolytic tumor viruses aren’t a magic bullet for cancer, but they will be an additional tool for combination therapy with drugs, surgery, and radiation," Barry said. "What is exciting is their potential to be self-amplifying drugs: Each cell infected by one virus has the potential to generate 10,000-fold more ‘drugs’ that can spread to other cancer cells. This amplification has the ability not just to spread cell killing but also to amplify the production of transgene proteins and immune responses by producing cytokines or antigens [and kill more cancer cells]."
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  L. Menotti, G. Nicoletti, V. Gatta, S. Croci, L. Landuzzi, C. De Giovanni, P. Nanni, P.-L. Lollini, and G. Campadelli-Fiume Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells PNAS, June 2, 2009; 106(22): 9039 - 9044. [Abstract] [Full Text] [PDF]
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