By David N. Leff
Most eponymic diseases are named for the clinicians who first described them. Alzheimer's and Parkinson's come to mind. There are a few exceptions, such as Lou Gehrig's disease (amyotrophic lateral sclerosis) and Woody Guthrie's disease (Huntington's chorea), which bear the monikers of their most famous victims.
On this basis, a case can be made for naming head and neck cancer "Sigmund Freud's disease." The illustrious founding father of psychoanalysis (1856-1939), an inveterate chain-smoker of cigars, had his cancerous jaw removed surgically. Freud kept right on smoking, until he succumbed to cancer of the jaw. This is one of the many facial and cervical tumor types called collectively squamous cell carcinoma of the head and neck. A roll call of these neoplastic maladies includes tumors of esophagus, larynx, middle ear, nasopharynx, oral cavity, tongue and tonsil. They wreak severe pain and difficulty swallowing or speaking.
The two main risk factors for these acquired malignancies are tobacco and alcohol, both of which enter the body via the oral and nasal routes, and course south along the neck. Head and neck cancer afflicts half a million patients a year worldwide. In the U.S., annual incidence is an estimated 40,300 cases, with 11,700 deaths - around 30 percent mortality.
Surgery, radiation and chemotherapy, the front-line treatments, succeed in only 30 to 40 percent of patients treated, but the tumors stage a comeback in one-third of such cases. After recurrence or metastasis, treatment can only be palliative rather than curative.
Now a devious new viral-based strategy has emerged, aimed at outright cure of head and neck cancer. The adenovirus (AV) in question is best known as a perpetrator of the common cold, and as a DNA-delivery vector in gene therapy attempts.
Cancer researcher Frank McCormick, then at Onyx Pharmaceuticals Inc. in Richmond, Calif., rejiggered the adenoviral genome to turn it into a selective slayer of tumor cells. McCormick is now director of the University of California Cancer Research Center in San Francisco. In his absence, a colleague of his, Martin McMahon, an assistant professor elsewhere at the Institute, explained McCormick's strategy to BioWorld Today.
Adenovirus Inveigles p53 To Kill
"When AV normally infects a cell," he recounted, "it needs to remove some of the cellular defense mechanisms that would prevent the virus from replicating. One of the key defenses a normal cell has to prevent viral growth is a protein called p53. AV contains two proteins, which, working in concert, serve to destroy the cell's tumor suppressor molecule, p53. This allows the virus the opportunity for unregulated replication.
"McCormick's rationale," McMahon continued, "was to delete one of those two proteins, E1B 55k, from AV's genome. So if you were to meet that engineered form of the virus that didn't have E1B 55k, it would no longer be able to deal with cellular p53, and the stripped-down virus would then be unable to grow in normal cells. The thing about human cancer cells," he went on, "is that a good 50 percent or more of them have lost p53 - that important mechanism for suppressing tumor cell proliferation.
"So an adenovirus that no longer has E1B," McMahon went on, "and thus cannot grow in a cell that has normal p53, in principle can grow in a cell that has abnormal p53 - which would be many cancer cells. By that rationale, McCormick made an AV that cannot replicate in normal cells, but which can replicate, and therefore destroy, tumor cells. Onyx named this cytolytic adenovirus ONYX-015."
The company supplied its new viral weapon to the University of Texas M.D. Anderson Cancer Center, in Houston, which mounted a Phase II clinical trial to test its therapeutic efficacy in head and neck patients. The results of this two-year study have just appeared in the August 2000 issue of Nature Medicine. Its title: "A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5 - flurouracil in patients with recurrent head and neck cancer."
The article's co-senior authors are David Kirn, who launched the trials at Onyx, and Waun Ki Hong, chairman of Head and Neck biology at M.D. Anderson (and president-elect of AACR, the American Association of Cancer Research). Its lead author, Fadlo Khuri, serves in Hong's department.
Cohorts Serve As Self-Controls
The Phase II trial enrolled 37 patients, 32 men and five women, ages 22 to 78. Of their number, 32 (86 percent) used tobacco; 34 (92 percent) alcohol. Treatment combined ONYX-015 injected directly into their tumors with two systemic, standard chemotherapeutics, cisplatin and 5- flurouracil. Each participant had at least two separate tumors, of which the larger received the combination therapy, while the smaller - the control - got only chemotherapy. Of the 37-patient cohort, seven dropped out for various reasons, leaving 30 for evaluation.
Just over half of all participants reported injection-site pain; about one-third experienced flu-like symptoms.
By six months, after two three-week cycles of treatment, none of the cohort that got the full treatment had disease that progressed, whereas all non-injected tumors did. Tumors shrunk in 25 of the 30 cases evaluated, most of them by 50 percent or more. Some lesions as large as 10 centimeters in diameter regressed completely. In six patients, the ONYX-015-injected tumor responded; the other did not.
"Whether this enhanced local control," the paper commented, "will be translated into a survival advantage remains to be confirmed by Phase III trials - but a median survival time of 11.5 months is encouraging."
Helen Kim, vice president of corporate development at Onyx, told BioWorld Today, "We have initiated a Phase III study in June of this year. We're looking to treat approximately 300 patients. It will take place in the U.S. and Europe. We hope to have from 30 to 60 centers, depending on the patient accrual rate.
Beyond head and neck, Kim related, "We have completed Phase I/II studies in treatment of liver metastases of colorectal cancer with ONYX-015. We have an ongoing Phase II trial with pancreatic cancer, and a completed study giving the virus via the intravenous route in advanced refractory solid tumors. Also ongoing trials in treatment of glioma, oral leukoplakia and cervical cancer."