Mar. 20, 2001 Chapel Hill - The University of North Carolina at Chapel Hill School of Medicine is one of nine medical centers nationally trying to determine if injections of a genetically modified common cold virus may be an effective treatment for recurrent head and neck cancer.
Under investigation is a form of adenovirus that's modified to selectively infect and destroy tumor cells only.
Unmodified, adenoviruses can infect and multiply in both cancer and normal cells, thereby killing all cells. One of the genes that enable the virus to replicate is E1B. This gene's protein inactivates the tumor suppressor gene, p53, which normally protects the cell from adenovirus infection. "Unless p53 is inactivated, adenoviruses cannot replicate," explained Wendell G. Yarbrough, MD, assistant professor of otolaryngology/head and neck surgery at UNC-CH. "About 50% of malignant head and neck tumors are made of cells with an inactivated p53 gene. Cancer cells are the only cells in the body in which p53 has been inactivated allowing for specific killing of cancer cells by the modified virus." Adenovirus with a mutated or deleted E1B gene will not produce the protein needed to inactivate p53. This means the virus replicates only in tumor cells, not in normal ones.
"And when this virus gets in a cancer cell with inactivated p53, it replicates, makes new adenoviruses, and then as part of its normal life cycle, it lyses or kills that cell and releases viruses that can then infect adjacent cancer cells," Yarbrough said.
Yarbrough, the principal investigator for UNC in this clinical trial, said therapy using E1B-mutated adenovirus ties in with his basic research on the gene ARF, an activator of p53. "In fact, we're now combining ARF with this virus to look at the effect of this combination on tumor cells."
The researcher notes that previous studies using adenoviruses as cancer therapy have relied on viruses unable to replicate. But the modified adenovirus developed by Onyx scientists in Richmond, California, and known as CI-1042, can multiply in cancer cells.
"That's why I was excited about a conditionally replication-competent adenovirus, because one of the major problems of adenovirus gene therapy, and adenovirus therapy in general, has been the problem with trying to ensure that all of the cancer cells get infected," Yarbrough said.
He points out that the clinical advantage of using a mutated adenovirus has been observed in many experimental models. And in one clinical study, the virus was injected directly into recurrent tumors that had failed all other treatments. Patients also received chemotherapy with cisplatin and 5-fluoraouracil. The study resulted in roughly 60% of tumors responding to treatment.
The new multi-center clinical trial is designed to treat recurrent head and neck squamous cell cancer that is amenable to direct injection. Some patients will be randomized to receive chemotherapy alone and others randomized to chemotherapy plus adenovirus. Pfizer, Inc sponsors this trial.
"The nice thing about most biological therapies, including this adenovirus, in combination with standard therapy is they don't increase toxicity to the patient. Research also suggests that adenovirus and chemotherapy may have synergistic anti-tumor activity," Yarbrough said.
Yarbrough's UNC collaborators in the clinical trial include Drs. Mark C. Weissler, Carol G. Shores, William W. Shockley, and Stephen A. Bernard.
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