An Oncolytic Herpes Virus for Nestin-Producing Glioma Cells

Abstract

New research shows that a virus designed to kill cancer cells can significantly increase the survival of mice with an incurable human brain tumor, even some with advanced disease.

The study used a genetically altered herpes simplex virus that infects and reproduces only in malignant glioma cells and kills them. The virus leaves normal tissues unharmed. Viruses that kill cancer cells are known as oncolytic viruses.

The findings were published in April in the journal Cancer Research.

E. Antonio Chiocca, M.D., Ph.D. "This is another step toward making oncolytic viruses more effective and safer for use in the treatment of cancer," says Dr. E. Antonio Chiocca, co-leader of the Viral Oncogenesis Program at the Ohio State University Comprehensive Cancer Center and director of OSU's Dardinger Center for Neuro-oncology.

"This is a preliminary study," Chiocca emphasized. "This virus cannot yet be used in humans. To go from animal studies to human studies is a very long process, especially for a treatment that uses viruses."

Malignant gliomas are cancers in the brain that progress quickly after diagnosis. They are nearly always fatal, Chiocca says. The average survival following diagnosis is about a year. They are usually treated using surgery, chemotherapy and radiation.

"Unfortunately, the average survival time for these patients has not improved in more than 30 years," says Chiocca, who is also the Dardinger Family Professor of Neurological Surgery and chairman of OSU's Department of Neurological Surgery.

He believes oncolytic viruses offer a promising new strategy.

Chiocca's collaborators for the study included Yoshinaga Saeki, associate professor of neurosurgery, who directed the research, and first author Hirokazu Kambara, a post-doctoral fellow.

The study began with a laboratory version of a herpes virus that was missing several genes. The virus could infect only malignant glioma cells, but once inside the cells, it reproduced, or replicated, poorly.

"Instead of making 1,000 copies of itself, it might only make 10," Chiocca says. The virus therefore had only a weak ability to kill cancer cells and shrink tumors.

For this study, Saeki, Kambara and Chiocca restored the virus's ability to replicate at high levels by returning one of the genes that had been removed from the virus. First, though, the researchers modified the gene, known as ICP34.5, so that it would be active only in cells that made a protein called nestin.

Why nestin? Usually, cells make nestin only during embryonic development. After that, it is absent from cells. But malignant glioma (and some other cancers) begin producing nestin again. This sets the cancer cells apart from normal cells and gave the researchers the trigger they needed.

The researchers tested the modified virus first in laboratory-grown malignant glioma cells. They found that the ICP34.5 viruses could again replicate at high levels.

Then the researchers tested the virus in mice with implanted human gliomas. In one set of experiments, the researchers gave the virus to the mice early, seven days after implanting the tumors. Untreated mice lived for 21 days after tumor implantation. Eight of 10 mice treated with the ICP34.5 virus survived 90 days after implantation. Two of 10 mice treated with a control virus survived 90 days.

The control virus was very similar to a type used in clinical trials testing viral treatment of malignant glioma. It was similar to the experimental virus, but it lacked the ICP34.5 gene.

But human glioma patients are usually diagnosed and treated later in the disease, after symptoms begin. The researchers therefore conducted an experiment that simulated that condition. They injected the virus into tumors 19 days after implantation and when the mice began showing symptoms, which is similar to the case in human treatment.

In this experiment, two of 10 animals treated with the ICP34.5 virus survived 24 days after implantation. Of mice treated with the control virus, all 10 had died by day 21, a statistically significant difference.

"The treatment extended the animals' lives by several days," Chiocca says. "If we could achieve a proportional increase in humans with malignant glioma, that would be a very significant advance."

Funding from the National Cancer Institute supported this research.

Chiocca was recruited to OSU last year from Massachusetts General Hospital and Harvard Medical School. He is nationally recognized as a leading investigator in the use of gene therapies for brain tumors and other central nervous system disorders.

The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute is one of the nation's leading centers for research on the prevention, detection, diagnosis and treatment of cancer. The OSU CCC-James encompasses six interdisciplinary research programs and includes more than 200 investigators who generate over $95 million annually in external funding. It is a founding member of the National Comprehensive Cancer Network, and OSU's James Cancer Hospital is consistently ranked by U.S. News & World Report as one of America's best cancer hospitals.