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Turning viruses into allies against cancer

To most, the mere mention of the word "virus" stirs up memories of pain, fever and varying levels of suffering. But in recent years, scientists have been trying to turn these long-time medical foes into allies in the fight against cancer.

Through genetic engineering, viruses are being re-programmed to take advantage of their natural abilities to infiltrate, commandeer, replicate and destroy, but only in tumor cells and not surrounding healthy tissue.

Several of these "oncolytic" (cancer-killing) viruses are in varying stages of development, including modifications of the virus that causes measles and another, the herpes simplex virus, responsible for those lip blisters known as cold sores.

In studies presented this week at the 96th meeting of the American Association for Cancer Research (AACR), researchers describe their latest studies with their engineered versions of these viruses.

Cold Sore Virus Modified to Halt Growth and Spread of a Variety of Tumors: Abstract 5292

A modified herpes simplex virus, built with a potent immune stimulant to thwart the spread of cancer cells, is being tested in patients with a variety of tumor types, including melanoma, breast, head and neck, and colorectal cancer.

In early clinical studies, the engineered virus -- developed by Biovex Ltd. under the trade name OncoVEX -- showed promise of causing necrosis (death) of tumors cells in most patients.

"Tumor necrosis was evidenced clinically and/or by histology in biopsies taken about two weeks after the final dose in a number of patients," said Jennifer Hu, M.B.B.S., a clinical research fellow at Hammersmith Hospital (Imperial College) in London, who conducted much of the study. "In some cases necrosis was considerable."

Like other oncolytic viruses, the modified herpes simplex virus used in these studies was engineered to attack tumors cells without harming surrounding healthy tissue. This virus also was further altered to increase its potency.

However, the Biovex scientists went one step further when they inserted into the virus the gene for a powerful antitumor immunity stimulant called GM-CSF, (granulocyte macrophage colon stimulating factor). Its job is to induce an immune response to any surviving cancer cells released during the initial viral attack, essentially preventing the spread of these cells to other parts of the body.

"This aims to treat metastatic disease and reduce tumor recurrence," said Robert Coffin, Ph.D., chief scientific officer at Biovex Ltd. While this has not been demonstrated in patients, the approach has show promise in pre-clinical studies.

In a phase I/II clinical trial, the scientists tested their modified virus in 26 patients, including eight with melanoma, 13 with breast, three with head and neck cancer, and two with colorectal cancer. Each patient, all in the later stages of their disease, received either a single injection of the virus, the volume depending on tumor size, or in later stages of the clinical trial, three injections separated by two to three weeks.

Aside from evidence of tumor necrosis, the scientists detected expression of GM-CSF in injected tumors.

"There were no obvious differences in the effects on the different tumor types," added Hu. "Following the promising data, this version of OncoVEX is now entering Phase II development in a number of tumor types."

The study's principal investigator was Charles Coombes, M.D., Ph.D., who heads the Cancer Research (UK) Laboratories and a professor at Hammersmith Hospital, part of Imperial College, where many of the patients in the study were enrolled.

Engineered Measles Virus Seeks Out and Destroys Liver Cancer Cells: Abstract LB-297

A weakened measles virus, modified with a protein that normally takes up iodine in the thyroid gland, is being studied to treat human liver cancer cells grafted in an animal model.

Scientists at the Mayo Clinic in Rochester, Minn., reported that the engineered virus seeks out and destroys liver cancer cells, leaving surrounding healthy tissue in tact.

The iodine "transport" protein attached to the virus acts as a kind of homing beacon for radioactive iodine, providing a second line of attack against the cancer cells, technically known as radio-virotherapy.

"These results clearly demonstrate the high potential of this modified virus to serve as a novel vector for cancer gene therapy of hepatocellular carcinoma," said Boris Blechacz, M.D., a research fellow in the Molecular Medicine Program at the Mayo Clinic and the study's lead investigator.

Liver cancer is one of the leading causes of cancer death worldwide, causing nearly a million deaths per year. Despite a variety of differing treatment approaches, its prognosis remains poor with a median survival of about 10 months following diagnosis. For this reason, scientists are anxious to find novel methods that could improve short- and long-term survival from this disease.

"The attenuated vaccine strain of measles virus is an oncolytic virus which has shown anti-tumor activity and tumor-selectivity in a variety of different tumor models," said Blechacz. "But its potential in primary liver tumors has never been evaluated."

In the first part of their study, the scientists studied the impact of their modified measles virus (MV-Edm) in liver cancer cell lines from human patients. Analysis of liver cancer cells removed from patients shows that these cells contain large amounts of the natural receptor for the measles virus, CD46. Overexpression of this receptor thus makes liver cancer cells ideal targets for the measles virus. The results confirmed widespread infectivity, toxicity and destruction among these cells, probably through apoptosis or programmed cell death.

When the modified virus was injected directly into human liver cancer cells grafted onto laboratory mice , scientists observed significant prolongation of life; complete regression was achieved in up to one-third of the treated mice.

During the second phase of their study, the scientists attached the iodine "symporter" protein to the MV-Edm and injected the newly engineered virus intravenously into the mice carrying the human liver cancer cells.

"Intravenous treatment with this combination followed by injection of radioactive iodine into the mice bearing the human hepatocellular cancer cells resulted in high uptake of the radioactive iodine at the tumor site," said Blechacz. "This provides the possibility of enhancing the therapeutic effect by co-treatment with therapeutic radioactive iodine."

Future studies should help scientists evaluate the efficacy and optimal delivery system of their radio-virotherapy vector.

"We expect this work will take another two years before this technology will be available for testing in patient studies," said Blechacz.


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Source:American Association for Cancer Research


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