The Big IF in Cancer

Will the natural drug interferon fulfill its early promise?

It can start in just one of the body's billions of cells, triggered by a stray bit of radiation, a trace of toxic chemical, perhaps a virus or a random error in the transcription of the cell's genetic message. It can lie dormant for decades before striking, or it can suddenly attack. Once on the move, it divides to form other abnormal cells, outlaws that violate normal genetic restraints. The body's immune system, normally alert to the presence of alien cells, fails to respond properly; its usually formidable defense units refrain from moving in and destroying the intruders. Unlike healthy cells, which stop reproducing after repairing damage or contributing to normal growth, the aberrant cells respect few limits or boundaries. They continue to proliferate wildly, forming a growing mass or tumor that expands into healthy tissue and competes with normal cells for nutrition. Not content with wreaking local damage, the burgeoning tumor sends out groups of malevolent cells, like amphibious invasion forces, into the bloodstream, which carries them all over the body. Some perish on their mission. But here and there, many of these mobile cells establish beachheads on healthy tissue and begin dividing, forming new tumors. Eventually the marauding cells infiltrate, starve and destroy vital organs, incapacitating and usually bringing death to their unwilling host. Cancer has claimed another victim.

This dread scenario is occurring with dismaying?and increasing ?frequency around the world. In the U.S. alone, 405,000 people will die of cancer and nearly a million new cases will be diagnosed this year. Nearly every family is affected; one out of every four Americans will eventually be stricken with the baffling disease. Progress has been made in treating some forms of cancer. Yet despite years of great effort and expense by government and private researchers around the world to understand and conquer the disease, the best that many cancer victims can hope for is to have their lives prolonged for a few years by one or a combination of three kinds of often unpleasant, debilitating and sometimes disfiguring treatment: surgery, radiation and chemotherapy. Two-thirds of all cancer victims eventually die of the disease.

Now, after years of agonizingly slow progress in cancer research, there is a growing and barely suppressed sense of excitement among medical specialists. Just as a fortuitous confluence of developments in rocket, electronic and computer technology resulted in the space feats of the 1960s and 1970s, recent achievements in chemistry, molecular biology and genetic engineering are contributing to what could be, in several years, a major advance in cancer therapy. If all goes well, they will make possible ample supplies of what is now a rare, extremely expensive, but promising new cancer drug: interferon, or, as scientists abbreviate it, IF.

The designation is appropriate, because doctors still precede their cautiously hopeful statements with serial "ifs." If longer-range tests show good results. If interferon can be manufactured in the massive quantities needed for effective treatment. If it proves not to have unexpected side effects. Should these and other ifs become fact, IF will be an ideal cancer drug, for it is a natural substance, produced in infinitesimal amounts by the body. Unlike existing treatments, interferon seems not to damage healthy cells or produce horrendous side effects. Its only apparent shortcomings seem temporary and confined to slight fever, fatigue, and a small decrease in the bone marrow's production of blood cells.

Even now, at ten medical centers across the U.S., the largest test ever of interferon is under way. Bought with an initial $2 million provided by the American Cancer Society (the most generous research grant in the organization's history), tiny quantities of the drug are being administered to some 70 patients with four different types of cancer ?most of them advanced?that were no longer responding to conventional treatment. As more interferon becomes available, at least an additional 75 victims will be treated.

Last week the first data from the test were revealed. The details were fragmentary, but the results looked promising. Of 16 patients with breast cancer that had metastasized (spread to other parts of the body), seven cases showed noticeable improvement, five of them enough to be classified as partial remissions. Tumors shrank substantially in three of eleven patients with multiple myeloma, a cancer of the bone marrow. Though it is too early in the treatment of patients with lymphoma (a cancer of the lymph system) or melanoma (skin cancer) to assess the effect of the drug, the attending doctors see encouraging signs. Discussing the early results, Frank Rauscher, head of research at the A.C.S., was emphatic. Said he: "The answer is yes. There is definitely activity against cancer. Abundantly, clearly, yes."

It is also abundantly clear that the big A.C.S. grant in August 1978 brought interferon instant respectability, accelerated worldwide IF research, and set off a flurry of activity in the executive suites and laboratories of the nation's drug companies. Impressed by the fact that the cancer organization thought enough of IF's prospects to invest so much of its scarce money in the test, industry decided to gamble on the drug's success. Pharmaceutical companies have now poured as much as $150 million into interferon research and production facilities. Their incentive was heightened last summer when the National Cancer Institute announced that it would buy as much as $9 million worth of interferon for further studies and invited bids from potential new manufacturers. The A.C.S. has since added $3.8 million to the IF pot.

Now hardly a week passes without some mention of interferon in the press. Last week the Boston Globe reported that M.I.T. researchers had developed a new mass-production technique that could reduce the cost of a dose of interferon to one-twentieth of its present cost. Earlier this month G.D. Searle & Co. announced plans to build a $12 million IF plant at its research facilities in Britain. Abbott Laboratories, Warner-Lambert, Merck & Co., and a number of other companies are also gearing up for interferon production. When Biogen S.A., a Swiss firm specializing in the new recombinant DNA (gene splicing) techniques, announced in January that it had induced bacteria to produce a facsimile of human interferon, the stock of Schering-Plough, a part owner of Biogen, rose almost eight points, to 37?. Says one prominent cancer researcher: "The drug companies know that there is a gold mine in interferon. They are scrambling like mad to produce it."

A gold mine, indeed. Most of the available IF is now obtained from the Finnish Red Cross and the Central Public Health Laboratory in Helsinki, which extract it from white blood cells separated from donated blood. The output in 1979 was minuscule, 400 mg (.014 oz.) gleaned from 45,000 liters (90,000 pints) of blood. The effort is so painstaking that, according to estimates by scientists at the California Institute of Technology, a pound of pure interferon would cost between $10 billion and $20 billion. That price will certainly decline as large companies enter the field with more efficient production techniques. As one Wall Street analyst predicts, "The market for the stuff is probably big enough for everyone to get a share. If interferon is used, it appears that it will be used in enormous quantities, so the companies that learn how to produce it and sell it the cheapest will reap enormous benefits from their research investment."

The substance that has caused all this excitement was discovered in 1957 by Virologists Alick Isaacs and Jean Lindenmann. Isaacs, who died of a nonmalignant brain tumor at age 45 in 1967, was investigating influenza viruses at London's National Institute for Medical Research. There he met Lindenmann, who had arrived from Switzerland in July 1956. Lindenmann, now head of experimental microbiology at the University of Zurich, stayed in London only a year. But it was time well spent. Over a cup of tea that August, the two scientists discovered a mutual fascination with a biological phenomenon known as viral interference. It was so called because doctors had observed that a victim of one kind of virus-caused illness practically never came down with another viral disease at the same time; the presence of one kind of virus seemed to inhibit infection by any other.

But why? Isaacs and Lindenmann had the answer by early the next year, a remarkably quick solution to a major scientific puzzle. In a series of experiments, they took pieces of the thin membranes that line the inside of chicken eggshells, grew them in a nutrient solution, and exposed them to influenza viruses. When they added other viruses to the culture, they found that the cells resisted further infection. True to form, the first set of viruses seemed to be thwarting the attack of the second. The researchers next removed all traces of viruses and chicken cells, leaving only the culture brew. They added this solution to a batch of healthy cells and "challenged" them with a new virus. The cells remained uninfected. It was apparent that the initial virus infection had stimulated the cells to produce something that interfered with further viral assaults; this substance remained behind in the solution when the original cells and viruses were removed.

Lindenmann decided to call the mysterious stuff interferon, a hybrid of "interference" and the suffix "on," which was in vogue among biologists, who were using such names as cistron, recon and muton to describe new genetic concepts. The initial discovery was made in November and duly recorded in Isaacs' lab notebook under the entry: "In search of an interferon." Lindenmann took it all in stride. Said he: "I thought it quite natural that when you did research you discovered things."

But the implications were staggering. Here at last, it seemed, was an agent that would mow down a broad spectrum of viruses, just as penicillin does with bacteria. Most laymen remained unaware of the discovery, but one notable exception was Dan Barry, artist of the Flash Gordon comic strip. That became evident when the first clinical use of interferon took place not in a hospital but in a 1960 Flash Gordon adventure. In that episode, spacemen infected with an extraterrestrial virus aboard a rocket ship far from home are pulled back from death's door by last-minute injections of interferon.

But many scientists had their doubts, one of them disdainfully calling the finding "misinterpreton." Recalls Microbiologist Samuel Baron, who worked with Isaacs in 1960: "It was too good to believe. Other inhibitors of viruses had been debunked, so they thought interferon was another false claim." Baron, from the University of Texas Medical Branch in Galveston, had his own doubts when he arrived in England to join Isaacs: "I remember saying to the technician, 'Let's see how this thing works.' It was so impressive that at the end of a week I was fully convinced of its potential. I rolled up my sleeves and went to work."

Baron was one of the few to persevere. He and other interferon researchers had little to go on, for there was practically no interferon available to be studied. The chemical is produced only in minute quantities in living cells, and extracting it proved difficult and costly, liabilities that are only now beginning to be overcome. Also, though all vertebrate animals produce IF, it seems to be species specific, meaning that it works only in the type of animal that produces it. Monkey interferon works only in monkeys, mouse in mice and human in humans. Thus, unlike the insulin extracted from cattle and pig glands and used by humans, IF harvested from animals does not work in people. Lindenmann continued working with IF for about three years, but then left it, believing its puzzles could best be worked out by biochemists. "I spared myself years of frustration," he says. Most of his colleagues, aware of the difficulties of interferon studies, considered his decision totally rational. Said one distinguished virologist at the time: "Anybody who abandons interferon research cannot be entirely stupid."

Throughout most of the 1960s, a handful of interferon enthusiasts continued working with only the tiniest amounts of material, gradually unlocking interferon's secrets. They found that it is a protein produced by cells in response to some stimulation, usually by a virus. To date, at least three varieties of IF have been identified. One kind is produced by leukocytes, or white blood cells. A second type is generated by fibroblasts, cells that form connective tissue in skin and other organs. (A prime source of fibroblast IF is the foreskin of circumcised infants.) The third, called immune interferon, is apparently made by T lymphocytes, soldier cells that attack invaders and are part of the body's immune system.* Each seems to work best in protecting cells similar to those that produced it.

The mechanism of IF's defense against viruses has also emerged. Explains Mathilde Krim, a researcher at Manhattan's Memorial Sloan-Kettering Cancer Center: "Interferon is a kind of chemical Paul Revere." When a virus invades a cell, instead of turning out the proteins needed to sustain the cell and other parts of the body, the manufacturing plant begins to produce carbon copies of the virus. Eventually bloated with the alien bodies, the cell almost literally comes apart at the seams and dies, spilling out its cargo of new viruses, which promptly move toward healthy cells to repeat the process and spread the infection.

Enter interferon. The initial infection somehow triggers the first cell into producing IF. In turn, the interferon assumes the role of an intercellular messenger; it passes through the cell membrane and moves on to warn surrounding cells of the viral invasion. The healthy cells respond by producing antiviral proteins, which meet any invader head on. The entering virus will not be able to replicate within the new cell; if it does manage to reproduce, its progeny find that they are unable to leave the cell. The cycle of infection is broken.

The small band of interferon researchers were able to produce or get their hands on enough interferon to analyze its nature, but the stuff was far too scarce or any significant tests on humans. Most of the credit for relieving that acute shortage goes to a stubborn Finnish virologist, Kari Cantell, who proudly admits that "interferon has been my hobby and main scientific interest for over 20 years." Cantell began his career by studying the role of leukocytes, or white blood cells, in fighting infection. He became intrigued when he learned from other researchers in 1961 that these cells could produce IF. By 1963 he had concluded that they might yield enough of the elusive substance to get research efforts off the ground. For the next ten years, he devoted all his time to developing the method that today supplies most of the world's leukocyte IF.

Cantell's manufacturing facility is unimposing, at best. It consists of a suite of labs in Helsinki's Central Public Health Laboratory. There, Cantell works with white cells derived from the 500 to 800 pints of blood donated daily to the Finnish Red Cross by citizens in and near the nation's capital. The Red Cross spins the whole blood in a centrifuge to separate its elements; the heavy red blood cells sink to the bottom, white cells settle just above, and the liquid plasma rises to the top. The Red Cross keeps the plasma and red cells for transfusions and turns the white cells over to Cantell. He infects the leukocytes with Sendai virus, an influenza-like virus harmless to humans, and incubates them at 37.5? C (99.5? F) for 24 hours. The resultant IF solution is centrifuged to separate out the white cells and partly purified to destroy the virus. What remains is a highly impure IF preparation; even after it is partly purified it consists of only one part IF for every 999 parts of other substances. To purify it totally is both impractical (99% of the interferon is destroyed) and prohibitively expensive. By last year Cantell and a small staff were turning out 400 billion units annually (one unit is the amount of IF that protects half of a cell culture in a laboratory plate from being destroyed by a test virus). That may sound like a lot, but daily doses of millions of units are needed for each patient being tested, and in the early 1970s Cantell's impure product did not go very far.

Still, researchers now had enough interferon to move studies out of the laboratory and into the clinic. In 1972 Virologist Thomas Merigan, of Stanford University, and a group of British researchers began studying IF's effect on the common cold. Soviet doctors were claiming success in warding off respiratory infections with weak sprays of IF made in a Moscow laboratory. Merigan and his colleagues gave 16 volunteers a nasal spray of interferon one day before and three days after they were exposed to common cold viruses. Another 16 volunteers were subjected to the same viruses without any protection. The results seemed miraculous. None of the 16 sprayed subjects developed cold symptoms, but 13 of the unsprayed did. There was one catch: at the IF strengths that Merigan used, each spray cost $700.

In the years since, Merigan and his Stanford team have successfully used IF to treat shingles and chicken pox in cancer patients. In other studies, IF has prevented the recurrence of CMV, a chronic viral disease that sometimes endangers newborn babies and kidney- transplant patients. Israeli doctors have also used IF eyedrops to combat a contagious and incapacitating viral eye infection commonly known as "pink eye." Researchers are now trying a combination of IF and the antiviral drug ara-A in patients with chronic hepatitis B infections. Interferon investigators have high hopes that the drug will be equally active against other viral diseases.

The concept that IF might also be effective against cancer may have occurred spontaneously to several researchers after the work of Isaacs and Lindenmann was confirmed. After all, it had already been shown that some animal cancers were caused by the polyoma virus. Though no human cancer virus has yet been definitely identified, some tumors seem to be linked to viral infections. In recent years, for example, it has been shown that women with the genital disease caused by the herpes type II virus are more likely to develop cervical cancer than those who are free of that virus.

One scientist was an American, Harvard-trained Ion Gresser, at the Institut de Recherches Scientifiques sur le Cancer in Villejuif, France. He made his own interferon by injecting viruses into the brains of laboratory mice; that stimulated the production of IF. After mashing the brains and processing them, he was left with a crude but potent solution of interferon. He gave the IF to a group of mice injected with a virus that causes leukemia, a blood cancer. After a month, the interferon-treated mice were in good health; those in an untreated control group had leukemia. Gresser then went on to demonstrate that IF actually prevented leukemia in mice that had been specially bred to develop it. Says he: "The interferon inhibited the multiplication of tumor cells."

News of Gresser's work inspired Hans Strander, a cancer doctor at Stockholm's Karolinska Institute, who had gone to Helsinki to work with Cantell in the '60s and had done his doctoral dissertation on IF production. In 1972, using IF from Cantell's lab, Strander began injecting it into children with osteogenic sarcoma, a rare and deadly form of bone cancer. Conventional treatment of this disease is to amputate the affected limb, in the hope that the cancer has not yet metastasized. In most cases, that hope is futile. Without additional treatment, the cancer spreads rapidly to body organs, killing almost 80% of its victims within two years. Strander has now treated 44 of these patients with IF after surgery. More than half are alive after five years (in a group that did not get IF, less than 25% are alive).

Strander has also used IF with seven children who have an appalling condition called juvenile laryngeal papillomatosis. In this disease, noncancerous, wartlike growths cover the vocal cords of the victim, sometimes filling up the entire larynx so that the child can barely breathe. The only treatment has been to cut them out, but they tend to recur quickly, requiring new surgery; one of Strander's patients had had 400 operations. Here too IF worked, though it was unclear whether its antiviral or antigrowth action was responsible. It diminished the growths in four cases and completely eliminated them in three. When the injections stop, though, the growths recur. Says Strander: "We're now trying to work out a maintenance schedule."

Strander's results sounded exciting to Dr. Jordan Gutterman, of the M.D. Anderson Hospital and Tumor Institute in Houston. He flew to Sweden to observe Strander's work, and soon became a convert. Says he: "There was no question. He was having good results." Back home, Gutterman obtained money from a private foundation to buy enough Finnish IF to try it on 38 patients with advanced breast cancer, multiple myeloma or lymphoma. Again the results were encouraging. Seven of 17 breast cancer patients had positive results, as did six of ten with myeloma and six of eleven with lymphoma.

Midway during this study, with some favorable response already obvious, Gutterman applied to the A.C.S. for money to expand the research. To support his appeal, he noted among other evidence the response of his first breast cancer patient: "She had a mass under her left arm, and couldn't raise her arm. Within 48 hours of her first injection, she could lift it." Another breast cancer victim is in remission after 15 months of interferon therapy. Gutterman also reports a wide range of sensitivity among patients, some showing improvement within 48 to 72 hours and a 50% reduction in the size of their tumors within three to four weeks after IF therapy. One patient with myeloma received interferon for three months with no apparent effect. But one month after the treatment ended, his tumor began to shrink. Presumably IF had had a delayed effect.

Gutterman's application to the A.C.S. reached the desk of Frank Rauscher, who before becoming the society's research chief in 1976 had been director of the National Cancer Institute for five years. At the institute he had been urged repeatedly to "do something about interferon." But Rauscher, himself a virologist, had moved cautiously. He did send an NCI team to Sweden to look at Strander's IF tests with bone cancer, and the institute co-sponsored a 1975 interferon conference in Manhattan. But during his tenure, Rauscher increased the NCI commitment to interferon by a scant $1 million yearly. Says he: "Quite frankly, I dragged my feet?in part because I didn't believe the results. They could be explained by other factors. Strander's study was not rigidly controlled; it didn't have the built-in scientific safeguards." He was also worried about possibly "killing something good" only because there was not enough of it for a really fair test. "I was about the most negative person in the country about interferon."

But by July 1978, as Rauscher surveyed the evidence assembled on his desk, his outlook had changed. New data from Strander, with better controls, were impressive. There were reports by other researchers of positive IF effects on tumors. Cantell had upped his production of interferon, and the evidence accompanying Gutterman's request for $1.5 million to buy IF was persuasive. Rauscher was convinced. He left his office, went upstairs to the A.C.S. executive offices and declared: "It's time to bite the bullet on interferon." The big drive for IF had begun.

In effect, it was like starting an armaments program without fully understanding how the weaponry works. If interferon is the body's Paul Revere, designed to warn against viral invasion and stimulate the defense forces, why does it also appear to work against cancer? Though viruses are suspect in some human cancers, interferon also seems to work against tumors generally thought to be caused by nonviral agents such as radiation and chemicals.

What scientists do know is that IF inhibits the growth of both healthy and abnormal cells by slowing cell division. Unlike most cancer drugs it does not kill malignant cells outright, but it somehow alters them so they stop proliferating. Another important difference: rather than killing cancer cells when they are rapidly dividing, IF works best when they are dormant and in the so-called resting stage. Interferon also seems to issue a call to arms to the general immune system. It marshals macrophages, scavenger cells that gobble up foreign material, and increases both the numbers and activity of another specialized group of lymphocytes, known as natural killer cells. All types of interferon boost the defense system, but the IF produced by T cells may do it best, perhaps because, as Pathologist Robert Friedman of the National Institutes of Health says, it is more of an "insider," a substance tailor-made by the immune system cells themselves. According to Samuel Baron, the Texas virologist, immune IF is 20 times more potent an antitumor agent than the interferon produced by fibroblast or leukocyte cells.

Whatever questions remain about both the role and effectiveness of interferon as a cancer drug, most could be answered if larger amounts of IF were available. Admits Gutterman: "We don't really know what we're doing yet. It happens with every new drug. In its early days penicillin was good at treating minor infections but not the big ones, like endocarditis [a bacterial infection of the heart valves]. It took years to figure out that it would work there too?but only at very high doses. But everyone said at first it would be crazy to try that level. There was just not enough material to work with to find out. The same is true of interferon. It's frustrating."

Some of that frustration may be eased over the next few years, as the pharmaceutical companies develop techniques for mass-producing interferon. Most of that IF will be produced initially by scaling up existing techniques: the stimulation of either white blood cells or fibroblasts cultivated in the laboratory. But less conventional routes are also being explored. One is to provoke the body into boosting its own manufacture of IF by injecting inducers, usually double strands of synthetic RNA* that resemble viruses. The method was tried in the 1960s by Maurice Hilleman and others at the Merck Institute. But inducers were virtually abandoned when they proved largely ineffective and, on occasion, highly toxic. A new inducer, though, has been showing some promising early results.

Other researchers are concentrating on unraveling IF's molecular structure. Caltech scientists are working with a "sequencing" machine that needs as little as ten picomoles (less than a millionth of a gram) of pure IF to determine the composition and sequence of the IF molecule's amino acid chain, which consists of about 150 links. Explains Molecular Geneticist Leroy Hood: "It's like having pearls of different colors on a string and clipping them off one by one and identifying the color of each."

So far, the Caltech researchers have sequenced 40 of fibroblast interferon's amino acid "pearls." When the structure of the chain is fully determined, which it probably will be before the end of 1980, chemists will try to re-create IF in the laboratory. That promises to be a difficult task: so long a chain tends to break apart in synthesis. But if they succeed, pharmaceutical companies may some day be able to mass-produce this and other types of interferon using only off-the-shelf chemicals.

Perhaps the most promising avenue to ample IF supplies is the recombinant DNA technique being tried by Biogen and other companies. Scientists chemically snip a gene from the DNA of one organism. The gene, which contains the code for producing a certain protein, is then chemically spliced into the DNA of another life form, usually a harmless laboratory strain of the common intestinal bacterium Escherichia coli. Now the genetically reprogrammed bug has the ability to produce something new. It begins cranking out the protein and, given the proper nourishment, making millions of carbon copies of itself, each capable of producing the same protein. Though each creates only a tiny amount, the cumulative output can be substantial. Biogen's accomplishment, brought off by Swiss Molecular Biologist Charles Weissmann and his international team of colleagues, was to re-engineer E. coli so that it would produce largely complete molecules of human leukocyte IF. At Harvard, Biochemist Tadatsugu Taniguchi, who first isolated an interferon gene while at the Japanese Foundation for Cancer Research, and Molecular Biologist Mark Ptashne seem on the verge of getting their restructured E. coli to spew out human fibroblast IF.

Despite all the recent achievements, the growing excitement and the favorable early test results, the verdict is not yet in on interferon. Even IF's most fervent advocates warn against prematurely raising the hopes of cancer victims and their families. They appraise IF's prospects in the subjunctive, peppering their comments with "if" and "would" and "could." Were interferon finally to prove an effective cancer drug, there would still be a long way to go. At least a few?and possibly quite a few?years will pass before it becomes widely available. "In terms of research," says Dr. Ernest Borden, a cancer specialist at the University of Wisconsin, "we're only about 2% of the way along toward widespread clinical application." And should interferon become plentiful, it would probably be used as a supplement to, rather than a replacement for existing treatment. Warns Dr. James Holland, of Manhattan's Mount Sinai School of Medicine: "There are no breakthroughs in cancer treatment." Then he adds: "Come back in a year and ask me about interferon then. I bet I'll have some really exciting things to tell you."

Indeed, the interferon bandwagon seems to be gathering momentum. According to last week's Boston Globe story, the new M.I.T. production technique could bring the cost of fibroblast IF down from about $50 to only $2.50 per million units. Says the A.C.S.'s Rauscher: "Right now it's costing something like $150 a day to treat patients, and a full course of treatment can go as high as $30,000 or more. This is very good news indeed." So it is. For even if interferon should only partly live up to its initial, most tentative promise, it would augment the sparse arsenal so far developed to combat the world's most terrifying and psychologically daunting disease.

*A coded molecule that works with the DNA master molecule in transcribing the genetic message and is also a basic constituent of many viruses.

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