By David N. Leff

Science Editor

Of all the malignancies that human flesh is heir to, the most pitiless are without doubt pancreatic cancer and melanoma.

Between the two, on a scale of 10, for untreatability and aggressive spread, cancer of the pancreas would score 11 or 12 over melanoma's 10.

The eminent onco-endocrinologist Elwood Jensen put it this way: "Pancreatic cancer is the most refractory and aggressive cancer, at least that I know of, with the possible exception of melanoma."

He pointed out that unlike melanoma, which starts out highly visible, "or prostate cancer, which is out where you can find it and test its progress, or mammograms for breast cancer, there is really no way to pick up anything that is wrong in the pancreas, until it really is too late."

A quarter-century ago, while at the University of Chicago, Jensen reported discovery of the estrogen receptor, of which the presence or absence in a woman with breast cancer could determine whether she would benefit from a mastectomy, or do better on hormone therapy. That differential prognosis is now standard medical practice.

As for cancer of the pancreas, Jenson told BioWorld Today, "There is nothing you can do for it; it seems to resist all kinds of chemotherapy." He added: "The only good thing you can say about pancreatic cancer is that once it's diagnosed, one doesn't live very long, and so doesn't suffer very much."

Pancreatic cancer causes about 25,000 deaths a year in the U.S., twice as many in Europe, and its mortality rate is on the rise.

This six-inch-long flattened cylinder of an organ lurks up against the back wall of the diaphragm, just under the stomach. It's the inaccessibility of this site that makes diagnosis so difficult until, too late, pain and alarming loss of body weight make the clinician think pancreas. By the time of this delayed diagnosis, the disease is so advanced that only three percent of patients live another five years.

Cigarette smoking and high dietary fat are risk factors for the disease, notes the National Cancer Institute (NCI).

Given the total lack of effective therapies, the NCI's "Treatment Overview" makes this perhaps unique statement: "The survival rate with any stage of pancreatic exocrine cancer is so poor that clinical trials are appropriate alternatives for treatment of patients with any stage of disease, and should be considered prior to selecting palliative approaches."

Elwood, now in a post-retirement research post at the University of Hamburg, Germany, reached a similar conclusion.

From In Vitro To In Vivo To Clinical

He and his colleague, Wolff Schmiegel, at the Ruhr University, in Bochum, Germany, had some years ago made a signal discovery: that a cytokine, tumor necrosis factor-alpha (TNF-*), caused the epidermal growth factor receptor (EGFR) on pancreatic tumor cells to multiply mightily.

The resulting dense forest of these antigenic receptors were so many sitting-duck targets for a specific cell-killing monoclonal antibody.

"This is something that really has no approach to any therapy," Jensen said, "so it seemed to us that trying to make use of that TNF-*-induced increase in the EGFR seemed to be one way to go.

"After trying it in cancer cell lines and obtaining significant tumor regression, up to complete remission, in nude mice," he recounted, "we decided to conduct a preliminary study in pancreatic cancer patients."

Jensen is senior author of the resulting paper, published in today's Proceedings of the National Academy of Sciences (PNAS), dated Nov. 11, 1997. Its title: "Cytokine-mediated enhancement of epidermal growth factor receptor expression provides an immunological approach to the therapy of pancreatic cancer."

Schmiegel, the paper's first author, set up a Phase I/II non-randomized clinical trial in his clinic at the Ruhr University. It enrolled 26 pancreatic-cancer patients with life expectancies on the order of three to four months from four German university clinical centers.

Sub-cohorts of the 26 subjects received fixed doses of TNF-*, plus graduated amounts of the EGFR-targeting antibody.

In the low-dose group, no patients survived longer than 26 weeks, but of the two high-dose recipients, one 66-year-old woman experienced a complete remission, living for fully three years, before relapsing and dying four months later. Without the experimental therapy, Jensen pointed out, her life expectancy would have been three to four months. Four other subjects had substantial partial remissions.

"I'm optimistic that this will provide a new approach," Jensen concluded. "People have tried immunotherapy before, but not combined with this cytokine stimulation of receptor density."

'Intelligent Approach,' But Apply Caution

At the NCI, in Bethesda, Md., research oncologist Simir Khleis focuses on developing systemic cancer vaccines. Anent today's PNAS paper, he told BioWorld Today: "Without having read their report it's difficult to comment. I would say," he continued that if -- that 'if' underlined 600 times -- that if their approach is meant to do what it's going to do, then anything for pancreatic cancer is a great advancement. This is especially true if, first, there is a response; second, the approach is pretty intelligent, if it does what it's meant to do."

On the side of caution, Khleis observed: "The question that has to come to mind is that TNF-* is a drug that leads to a lot of side effects. That should be taken into consideration. Because when you give TNF-*, it not only increases EGFR in the pancreas, but in other, normal, tissues as well."

So far, the front-running treatment for pancreatic cancer is a gene-therapy construct, Onyx-015, which Onyx Pharmaceuticals Inc., of Richmond, Calif., has in a Phase I clinical trial. (See BioWorld Today, Aug. 14, 1997, p. 1.)

"So far," the company's president and CEO, Hollings Renton, told BioWorld Today, "we've treated 15 patients in that study, which is under way at the University of California, San Diego. We plan on 25 subjects, and should complete enrollment by next quarter. So by the middle of next year, we should be disclosing results."

Onyx-015, Renton explained, "is an engineered adenovirus deletion mutant, which can't make the 55-kilobase part of the viral gene that inactivates the p53 tumor suppressor. The concept is," he continued, "that we have created a virus that will not grow efficiently in normal cells, because almost all cells have p53. However, in a tumor cell that has lost p53 function, that virus will grow quite nicely."

As regards the just-published German trial, Renton observed: "This is one complete remission out of 26 patients, so there is some effect. But the question is: Does it leave room for other therapies? -- which it sounds like it probably does." *