MEDICINE

The advance against cancer

JOHN BARBER December 16 1985
MEDICINE

The advance against cancer

JOHN BARBER December 16 1985

The advance against cancer

MEDICINE

The effect was electrifying. Immediately after Dr. Steven Rosenberg announced the dramatic results of an experimental cancer treatment using the hormone Interleukin-2 (IL-2) last week, thousands of desperate people began telephoning the National Cancer Institute in Bethesda, Md.

The phone lines at the sprawling complex were jammed as dying cancer patients, their relatives and doctors grasped at a final chance for a cure.

One doctor called to say that his patients were reluctant to continue radiation therapy and were demanding “the Rosenberg method.” But the personable 45-year-

old cancer surgeon did -

his best to diffuse the excited speculation that he had found the cure for cancer. To that end, he continually emphasized the experimental nature of his treatment, its cost, its side effects and the fact that it would remain unavailable to all but a handful of patients for years to come. “This is not a cure for cancer today,” he told Maclean's. “It is just a first step. ”

Reacting to the news, many other researchers expressed similar caution. Dr. Robert Mayer of the Dana-Farber Cancer Institute in Boston declared, “I would be very reluctant to put it up in neon lights and call it a major advance.” Other specialists recalled the excitement over interferon, a protein that was greeted as a miracle cancer cure in the 1970s but has yet to fulfil its promise. Still, the importance of the Interleukin announcement was undeniable. Said Dr. Frank Rauscher, senior vice-president for research at the American Cancer Society: “I think this is terribly exciting and terribly important, and it is rare that you can use both of those words in one breath.” Added another Washington cancer expert, who asked not to be identified: “Of course, everyone is being very cautious.

They have to be. But many of us believe that this could be it. The big one.”

Despite the fact that Rosenberg’s team has treated only 25 patients, no cancer-fighting drug has ever produced such impressive results as those achieved with the complex Interleuken-2 therapy. The patients Rosenberg began testing last year all suffered from advanced cancer which conventional therapies had not _

cured. While 14 patients Paetkau: caution did not respond to treatment, the tumors of 11 people shrank by more than 50 per cent. In one case the treatment apparently eradicated a case of melanoma, a dangerous form of skin cancer which had spread through a woman’s body. In another patient three lung growths disappeared after treatment and two others shrank significantly, allowing doctors to remove them surgically.

More importantly, the trial introduced an en-

tirely new weapon into the fight against cancer. Said Rosenberg: “This is a new way to treat cancer. The standard ways—surgery, radiation and chemotherapy—have been around for a long time, but there have really been no whole new kinds of cancer treatment developed for decades.”

One of the most encouraging aspects

_ of the new treatment is

its reliance on the body’s natural defences to fight off cancer. In an article published in last week’s edition of the prestigious New England Journal of Medicine, the researchers wrote, “For the first time, we can take the immune system of a patient, alter it and use it to cause regression of a tumor.” By manipulating the immune system itself, the researchers were able to devise a treatment that singles out cancer cells for destruction.

By contrast, conven-

tional chemotherapy destroys cancerous and noncancerous cells almost indiscriminately. Even more remarkably, the treatment proved effective against a variety of cancer types. But the NCI study did more than demonstrate the promise of Interleukin-2. It also raised new hope that several similar tumorcombatting compounds —including some that are currently being tested —will one day be able to join Interleukin-2 in a whole new arsenal of sophisticated “immunotherapies.” Those

include tumor necrosis factor (TNF), a naturally occuring protein which activates parts of the immune system that Interleukin-2 does not affect and which has been shown to kill cancer cells while leaving normal cells intact. As well, several small U.S. companies are at the forefront of research of immunotoxins: genetically engineered substances which seek out cancer cells, penetrate the cell surfaces and poison them.

Like TNF, Interleukin-2 belongs to a group of chemicals called lymphokines which researchers first identified in the 1970s when they became more capable of observing the immensely complicated immune system at the molecular level. Lymphokines, including Interleukin-2, are secreted in minute amounts by white blood cells when the cells detect infections. They are “signal proteins” that alert other white blood cells in the body to a threat and stimulate them to release substances to attack it. But manipulating this process only became practical when scientists learned to mass-produce synthetic lymphokines with genetically engineered bacteria.

In the NCI’s experimental program,

Interleukin-2 therapy begins when patients are attached via an intravenous line to a blood centrifuge. During a four-hour period the machine extracts some 10 billion white blood cells from the patient while returning red blood cells through another intravenous line. Meanwhile, the researchers add a large amount of synthetic Interleukin2 to the white blood cells, and within three days this process transforms them into what Rosenberg calls “lymphokine-activated killer cells.” When

re-injected into the patient, the killer cells immediately begin attacking tumors with a degree of force that an unaided immune system could never attain. And in a final step, the researchers inject the patient with pure Interleukin-2 to intensify and prolong the combat.

Still, the patients whom Rosenberg treated all suffered what he acknowledge were “severe side effects” as they underwent the cell extractions and reinjections. The worst effect during Interleukin-2 treatment—apart from a patient’s month-long hospital stay—is fluid retention which in extreme cases can cause breathing failure. Indeed, Rosenberg told William Lowther of Maclean ’s, “there is a lot of toxicity associated with the treatment.” Compounding that problem is the high cost —upward of $20,000 per patient. In addition, Rosenberg believes that the procedure’s complexity will prevent widespread repetition of his experiment: at the moment he can only treat eight people at a time. Added Rosenberg: “Solving the problems is going to take a lot of hard work. We have a lot of ideas of ways to overcome some of them, but I think we are talking years

before this treatment will be widely applicable.”

Still, that work will begin from a broad-based foundation. Several other research teaftis in countries around the world, including Canada, are studying the promise of Interleukin-2 as intently as the scientists at the National Cancer Institute. Dr. Vern Paetkau of the University of Alberta, for one, began using it to shrink tumors in mice in 1979. And dozens of human trials similar to Paetkau’s now are under way. The San Francisco General Hospital has used it in an attempt—so far unsuccessful—to combat Alps, or Acquired Immune Deficiency Syndrome. And at the Memorial Sloan-Kettering Cancer Center in New York, Interleukin-2 is now being tested on several dozen patients with advanced cancer. There, researchers are administering Interleukin-2 without taking the extra step of extracting and enriching white blood cells. The reason: Dr. Jonathan Kolitz told Maclean’s that the sixmember research team hopes that its tests will help determine the body’s tolerance for the drug and the severity of its side effects. And he added that the simplified treatment has already produced some results in “some antitumor activity.”

Doctors at the Marcello Malpighi Hospital in Bologna, Italy, have reported impressive results from Interleukin-2 therapy. Last year they injected 10 patients with the substance and achieved total tumor regression in three of them. Two others experienced 70-per-cent regression, a sixth patient had to have his bladder removed, and four others experienced no change. During their research the five-member Italian team found that simple IL-2 injections were inadequate to combat cancers, and as a result they have concentrated on injecting the substance directly into the tumors. Declared Dr. Giancarlo Pizza: “Theoretically, it is an extremely important breakthrough in the approach to the treatment of cancer. From a practical point of view, so far the results have been sensational.”

For his part, Rosenberg said that his team will soon begin co-operating with several U.S. university hospitals to develop the NCI treatment further. He noted that only a few institutions currently possess the proper equipment to duplicate his experiment, but the institute is already studying ways of making the technique more widely available. One approach is the development of better machinery to ease the extraction of white cells from the patient’s body.

At the same time, a cancer treatment based on a patentable synthetic hormone offers the prospect of generating huge profits for private enter-

prise. To that end, many genetic engineering companies are now working toward commercial development of such lymphokines as Interleukin2—substances which they helped develop for the NCI. Indeed, lymphokines are the primary business of Seattlebased Immunex Corp., which produces Interleukin-2. Immunex president Stephen Duzan said that his company has been involved in testing Interleukin-2 on human cancer patients for two years and is currently conducting five trials in conjunction with the NCI. The company is also carrying out other private trials along with Swiss-based drug company Hoffmann-La Roche. Duzan would not reveal the results of those incomplete tests but he is hoping that the research will yield a practical therapy by 1988.

And Cetus Corp. of Emeryville, Calif., another genetic engineering firm which supplies the NCI team with a patented brand of Interleukin-2, is also involved in conducting trials of the substance with patients. Dr. Edward Bradley, the company’s director of clinical biology, said that he had doubted Interleukin-2’s worth last year but test results since then have caused him to change his mind. Said Bradley: “In the next year or two, people are going to realize that this really works, that what scientists have been saying all along is true.”

The most intense competition among private corporations involves the search for other lymphokines that can be genetically engineered for use in new treatments. Cetus is “mining the immune system from every angle,” said company president Robert Fildes. Both Cetus and another firm in the field, Genentech Inc. of South San Francisco, are testing tumor necrosis factor. “Tumor necrosis factor has a very potent effect,” said Dr Jordan Gutterman, of Houston’s M.D. Anderson Hospital and Tumor Institute. “It kills cancer cells and it leaves other cells alone. I think that as we get to understand lymphokines more and get them working in combination, we are going to have a major impact on cancer therapy.”

Supplementing the new research into lymphokines is the ongoing quest for other cancer treatments using substances known as immunotoxins. The technique makes use of antibodies which lock on to foreign substances and attack them directly—or signal their presence to killer cells within the immune system. Researchers in dozens of testing programs around the world have already succeeded in attaching potent toxins to cloned antibodies which then seek out—and poison—specific tumors. Now, many of those teams are investigating the possibility of using those antibodies in conjunc-

tion with lymphokine-based therapies.

For the most part, the basic research in both immunotoxins and lymphokines has yet to yield proven treatments. But one company, Biotherapeutics Inc. of Franklin, Tenn., is pushing ahead with experimental treatments that use both techniques on a select group of patients. Company president Dr. Louis Berneman told Maclean’s that his eagerness to proceed quickly has annoyed some scien-

tists. Still, the firm has attracted such top researchers in the field as Dr. Robert Oldham, the founder and former director of the NCI immunotherapy program. Said Berneman: “We believe that the current revolution of biologicals is such that patients who have real problems should have access to these emerging technological advances.” Biotherapeutics has started tests on about 30 patients in a complex program that begins with the analysis of a patient’s tumor cells to determine which therapy will be most effective against the cancerous growth. Then, if necessary, the researchers will design a specific toxic antibody in order to attack only those cells. But because the process can take up to one year to com-

plete, Biotherapeutics patients must be in fairly stable health. As well, they must be rich: custom-designing an antibody treatment will cost $35,000 alone. Said Berneman: “At this point, only those patients who are financially independent can take advantage of our treatment. We apologize for that but there is nothing we can do about it.” The company has also developed an Interleukin-2 treatment that Berneman says is similar to the procedure followed by Rosenberg. Berneman’s confidence reflects his belief that so-called biologicals—including Interleukin-2, tumor necrosis factor and immunotoxins—“are going to be the approach for cancer treatment.” But even the most enthusiastic researchers say that their work is only just beginning. Said Edmonton’s Paetkau: “People who talk about using this so-called immune therapy against tumors are fully aware that we know so little about these things that it is conceivable we could destroy the immune system rather than enhance it.”

Indeed, most researchers say that more extensive tests will be needed before they can judge Rosenberg’s work. And Dr. James Rusthoven, a cancer researcher at Toronto’s Sunnybrook Medical Centre, said that the new treatment may not prove as effective against solid tumors because those growths contain many inactive cells that may not be susceptible to attack by the killer cells. And Dr. Gordon Mills, an immunologist at the Toronto General Hospital, said that the effect of the treatment may not be permanent for cancer patients. Said Mills: “It may not prolong their lives.” Added Dr. Tarunendu Ghose, a leading cancer researcher with the Dalhousie University School of Medicine in Halifax: “There is so much false hope and false expectation that science is demeaned.” Unfortunately, science is also frequently defeated by the ravages of cancer. And to many researchers that justifies desperate measures. Said Paetkau: “The fact of the matter is, if you have patients who are going to die anyway, why not try it?” Presumably, that simple logic motivated many of the callers who telephoned the National Cancer Institute last week—in vain. Said one harried nurse: “At this time we cannot do anything for them. And the tragedy is that they don’t have the time to wait. They haven’t got five years.” But if Rosenberg’s treatment and similar immunotherapies fulfil even a fraction of their promise, they will diminish the grasp of a disease which last year claimed more than 40,000 lives in Canada alone.

-JOHN BARBER with DAVE SILBURT in Toronto, WILLIAM LOWTHER in Washington, LENNY GLYNN in New York, SARI GILBERT in Rome and CHRIS WOOD in Halifax

JOHN BARBER

DAVE SILBURT

WILLIAM LOWTHER

LENNY GLYNN

SARI GILBERT

CHRIS WOOD