Toward Cancer Control

WHEN Mrs. Mary Brown, a plump, cheerful housewife from Dallas, had her first bout with breast cancer seven years ago, her doctors knew exactly what to do. Following the accepted procedure, they performed a radical mastectomy, removing the affected breast, the underlying muscle tissue and the nearby lymph nodes. Then they subjected her to intensive radiotherapy, hoping that the X-ray bombardment would kill any residual cancer cells. But when cancer recurred at the operation site two years ago, and raised reddish, golf-ball-sized lumps on the flat area where her left breast had been, the doctors were stymied. Surgery was out of the question; the lumps were evidence that the cancer had spread too far. So was X-ray treatment. Mrs. Brown (not her real name) had already had so much exposure to X rays that any more could do serious damage to her healthy tissues. Thus, when even anti-cancer drugs failed to halt the spread of the disease, Mrs. Brown turned in desperation to a new and still experimental treatment.

The treatment, called immunotherapy, uses a biochemical strategy designed to trick the body’s own natural defenses into fighting cancer. In Mrs. Brown’s case, doctors deliberately exposed her to attenuated tuberculosis bacilli, figuring that if they could make her body resist them, it might resist the cancer as well. The strategy worked. Shortly after treatment began, her lesions began to shrink and disappear. Today Mrs. Brown has only a few lumps on her chest. None of her doctors will say that she is cured, but all agree that without immunotherapy she probably would not be alive today.

Mrs. Brown’s treatment is one of the most dramatic applications of the rapidly expanding science of self-immunology—the study of the body’s natural defenses against disease. That science is one of the most promising weapons yet developed by doctors in their long fight against cancer, which this year alone will afflict an estimated 650,000 Americans and kill more than 350,000. The older techniques—surgery, radiation and chemotherapy (drug treatments)—have been used successfully in bringing some cancers under control. But surgery usually results in unsightly and handicapping mutilation, radiation can destroy healthy as well as cancerous tissue, and chemotherapy produces unpleasant and dangerous side effects. Immunotherapy, which so far seems to have none of these disadvantages, could thus prove to be the ideal approach.

Whether immunology fulfills this promise and becomes a major part of medicine’s approach to cancer depends in large part on a harddriving, affable egotist named Robert Alan Good. A lanky (6 ft. 2 in.), generally rumpled man with an insatiable curiosity and an almost uncanny ability to assimilate any information that passes his way, Good, 50, is both a pediatrician and a Ph.D. in anatomy. He believes that immunology holds the key not only to controlling cancer but to preventing and curing many of man’s other ills.

Good is the foremost student, practitioner and advocate of immunology in the U.S. today. His own research, most of it carried out at the University of Minnesota, has been responsible for much of medicine’s current knowledge about how the immune system functions. His writings have helped spread the word about the new science; he is coauthor or editor of at least a dozen books on the subject, including two that are considered standard texts, and well over 1,000 articles. His clinical work has led to the development of techniques that successfully overcome malfunctions of the immune system.

Good recently moved from Minnesota to New York to become director of the largest privately operated cancer-research operation in the country. As the new president and director of the Sloan-Kettering Institute for Cancer Research and director of research at the Memorial Sloan-Kettering Cancer Center, he will continue his work in immunology, aiming toward understanding and controlling cancer. Those who are familiar with his ingenuity and energy predict that he will ultimately achieve his goal.

Fifth Column. Good’s achievements in immunology rest on a broad foundation of work by other scientists dating back to 1796, when the British Physician Edward Jenner inoculated an eight-year-old boy with fluid from a cowpox pustule in a successful attempt to give him resistance against the more virulent smallpox. Jenner knew nothing about the immune system, but he had recognized that milkmaids who frequently came in contact with cows suffering from cowpox seldom contracted smallpox. Scientists began to suspect that the body had a mechanism for identifying and combatting disease agents only after Louis Pasteur discovered the existence of bacteria and in the 1850s propounded the germ theory of disease.

That mechanism was still a mystery in 1891, when Dr. William Coley, an American surgeon, first observed the beneficial effects of certain infections on patients with cancer. Coley began injecting patients with mixed bacterial toxins to induce responses that might alter the course of the malignancy, and without fully understanding what he was doing, succeeded. In 1893, he injected his toxin into a 16-year-old boy with inoperable cancer and was rewarded with a demonstrable success: the tumor shrank and, over a period of a few months, disappeared. He treated some 250 other patients who also improved and survived for another five to 72 years. But despite the results, Coley’s work, which was far ahead of its time, generally went unrecognized.

Outlaws. But immunology was gradually becoming a science. The existence of antibodies—agents produced by the body in response to the challenge of disease-causing organisms—was discovered at the end of the 19th century. In the 1940s, doctors finally recognized that a badly functioning immune system, or the absence of one, can leave the body virtually defenseless against infection from without. But it was not until the early 1950s that Sir Frank MacFarlane Burnet, an Australian, theorized that the way the body manages to cope with the enormous range of disease organisms is through its ability to recognize itself and to reject everything that is nonself (see box page 67).

A few years later, Burnet and Dr. Lewis Thomas, who has just been appointed president of Memorial Sloan-Kettering Cancer Center, suggested a relationship between the immune system and cancerous growth. They postulated that in addition to protecting the body from invaders, the immune system has the duty to police cell growth and prevent the survival and replication of abnormal or “outlaw” cells.

As Burnet and Thomas saw it, the body, in which cells are continually replicating themselves, produces anywhere from tens to hundreds of abnormal, genetically different and potentially cancerous cells each day. Ordinarily, the immune system recognizes these biological fifth-columnists as “foreign” because they are genetically different; it destroys them before they begin dividing and reproducing. But when the defense mechanism is weakened, for whatever reason, it fails to do away with the errant cells, either because it cannot recognize them or because it is incapable of attacking them. That gives the outlaw cells (which are apparently not under the same genetic restraints as normal cells) the opportunity to run wild. They reproduce themselves at an extremely rapid rate, invade normal tissues, and, if not destroyed, cut out or arrested, eventually kill.

Some of the evidence that cancer thrives when the immune system is defective is purely circumstantial. For example, the disease strikes hardest at the aged or very young, the two groups whose immune systems tend to be weakest. Cancer on rare occasions has also been known to undergo spontaneous remission, an indication that some mechanism has acted to inhibit its growth.

But much of the evidence is more scientific. Good and his co-workers have observed a high correlation between cancer and the so-called immunodeficiency diseases, which leave their victims unable to resist infection. They speculate that eventually it will be found that all cancer patients suffer from some impairment of their ability to resist disease. “In order for cancer to occur and persist, there must be a failure of the immunological process,” says Good. “We’ve never found a cancer patient in whom something wasn’t screwed up immunologically.”

Other research tends to support Good’s theory. A study conducted at the University of California at Los Angeles showed that only one out of three patients about to undergo surgery for cancer was able to respond to a skin test used to determine if normal Immune reactions occur. Kidney-transplant patients, whose immune systems are suppressed by drugs to prevent rejection of the new organ, are more susceptible to certain malignancies than others in the same age groups.

The American College of Surgeons/National Institutes of Health’s organ-transplant registry studied more than 8,000 transplant patients and found 77 cases of cancer, 17 of which were a bone-marrow malignancy called reticulum cell sarcoma. Significantly, that disease occurs about 100 times more frequently in transplant patients than it does in members of the general population, according to a report by doctors at the Medical College of Virginia of the Virginia Commonwealth University.

Why these immunological problems occur has long been a mystery. But lately researchers have been finding some clues that could lead to its solution. Doctors at Sloan-Kettering Institute have discovered that some cancer cells fail to produce antigens, or markers identifying them as foreign, and thus avoid the body’s recognition mechanism. There is also speculation that larger cancers shed so many antigens that they simply overwhelm the immune system.

Drs. Karl and Ingegerd Hellstrom, Sweden’s husband and wife team now working at the University of Washington in Seattle, have found that in some cancer patients there are complexes known as “blocking factor” that prevent the immune system from attacking cancers. They have also discovered “unblocking factor” as well, raising hope that some method may be developed to free those immune systems inhibited by blocking agents.

Other doctors, meanwhile, have borrowed a leaf from Coley’s book and have been trying, with some success, to awaken sleeping immune systems to combat cancer. The techniques of this approach vary widely. Some doctors still use Coley’s bacterial-toxin formula; others inject vaccine made from killed mumps virus and diphtheria bacteria. Many, however, prefer a live-bacteria tuberculosis vaccine called BCG (for Bacillus Calmette-Guerin, after the Frenchmen who developed it).

Memory Jogger. BCG is not an anti-cancer drug as such. But it does appear to be a powerful immunopotentiator, or tool for turning on the immune system. When injected into patients with either natural or acquired immunity to tuberculosis, it jogs their immunological “memory” of the disease and produces a generalized immune response. Injected directly into cancer lesions, it can cause a responsive immune system to send anti-tuberculosis antibodies to the scene to fight the invaders. In some patients, this defense against bacterial attackers destroys cancer cells as well.

Several doctors are now using BCG for cancer immunotherapy. Dr. Donald Morton of U.C.L.A. has used BCG to hype up the immune systems of patients suffering from malignant melanoma, a cancer that first appears on the skin and spreads rapidly to other parts of the body; some of his patients have been free of the disease for two years or more.

Dr. Georges Mathé, a leading cancer researcher at the Paul Brousse Hospital at Villejuif, near Paris, has been using BCG since 1964. He administers it as part of a double-barreled approach to treating patients with acute lymphoid leukemia, a cancer of the blood-forming tissues that tends to further depress and obliterate the patient’s already weakened immune responses. Mathé begins with chemotherapy, using cell-destroying drugs that kill rapidly proliferating cells (and thus destroy cancer cells more quickly than normal ones) to reduce the size of cancers from billions of cells to 100,000 or so. Then he uses immunotherapy in an effort to make the body root out the residual cancer.

Dr. Edmund Klein of Roswell Park Memorial Institute in Buffalo has used BCG to stimulate an immune reaction against malignant melanoma, mycosis fungoides and other cancers that originate on the skin, as well as against such deep-seated tumors as breast cancer. He has also experimented with vaccines made from tumors similar to those of the patient, injecting the substance into cancer victims in the hope of triggering not a general immune reaction but one that is specifically directed against the cancer. Of those patients who responded immunologically, most showed marked improvement.

Dr. Virginia Caspe Livingston of the University of San Diego has also used such vaccines in patients with breast cancer and cancer of the thymus, and has achieved remissions. Dr. Loren Humphrey, chairman of the department of surgery at the University of Kansas School of Medicine, has evaluated 96 patients who have received injections of cells from people with tumors similar to their own; more than 20 have had partial remissions and three now appear completely free of disease.

Results like these have led some researchers to regard immunotherapy as one of the most encouraging developments in decades, and an important tool for the physician. “Immunotherapy used to be a dirty word in cancer,” says Klein. “No one thought it worked. Now it has become respectable.”

Overkill. But it still has a long way to go. Doctors are not yet sure whether the commonly used methods, which rely primarily on nonspecific immune stimulation to produce selective tumor destruction, represent a form of immune-logical overkill. Says Klein: “It’s sort of like alerting the whole damned U.S. Navy to keep one foreign destroyer from entering one harbor. It’s effective, but it may be unnecessary.” Furthermore, doctors cannot make immunotherapy work for all patients. They have no sure way of knowing who will respond until they begin treatment.

Even when such problems are solved, no one sees immunotherapy as completely supplanting other, more traditional methods of treatment. The technique seems to work best against small, localized cancers; surgery, radiotherapy and chemotherapy are still the preferred methods for dealing with large or widespread malignancies. But even when these methods are used, immunotherapy may still be necessary to cope with residual cancers. Says Dr. Lloyd Old, vice president and associate director of Sloan-Kettering Institute: “What we can do well right now is eliminate massive amounts of cells. But getting rid of 90% of a cancer, even 99%, isn’t enough; if there’s one cell left, it can produce millions more cells. Immunotherapy offers a way of getting at these residual cancers and preventing them from spreading.”

Despite the heady progress, few researchers think in terms of “curing” cancer, particularly in light of the widely held view that the body is constantly producing abnormal cells. “Let’s think of control of cancer rather than cure,” says Old. “Cancer is not a killing disease; what kills is progressive cancer. What we’re trying to do is not eliminate cancer but establish an equilibrium between cancer and its host.”

That, in essence, is what Good is uniquely qualified to do. He first became interested in medicine at the age of five when his father, a Minneapolis high school principal, developed what proved to be a fatal cancer. “I was very impressed with the doctor who came to take care of him,” says Good. “I never wanted to be anything but a doctor after that.”

The path to a degree in medicine proved arduous. The second of four sons in a fatherless family, Robert Good had to earn his own way through the Depression by raking leaves, shoveling snow and running a newspaper route. Impressed by Good’s ambition and industry, a Minneapolis businessman helped pay his way through medical school at the University of Minnesota.

While a student, he was stricken with a paralytic disease (doctors diagnosed it as poliomyelitis but Good thinks it was Guillain-Barré syndrome, which generally produces a less permanent form of paralysis); whatever it was, it left him partially paralyzed. Dropped from the class roster by professors who felt he would be unable to keep up his grades, he was restored only after he promised to withdraw voluntarily if his grades dropped below A. They never did. Through exercise, Good rehabilitated himself to the point where he has only a slight limp to show for his illness. He generally wears ankle-high sneakers, which he finds more comfortable than shoes, around the lab. His preference for another Good sartorial trademark—a turtleneck sweater instead of a shirt and tie—is purely personal. Says he: “I’ve never been convinced that a necktie has any real function except to get in the way.”

Toughness. Good’s interest in immunology dates from a chance discovery during medical school. Lacking enough fresh, uninfected rabbits for some research he was conducting, he used some animals he had infected with herpes viruses in an earlier experiment. His experiment, designed to elicit an allergic reaction, instead depressed the animals’ immune systems, which had kept the viruses under control. As a result, the viruses became active and the rabbits developed encephalitis. The results so intrigued Good that he combined studies in biology with his medical education and received his Ph.D. and M.D. degrees together in 1947.

Convinced that good research starts at the bedside rather than in the laboratory, Good opted for pediatrics because it would give him an opportunity to study immune system defects, which are most often found in children (victims usually die of disease well before adulthood). “Besides,” says Good, who admits that he has been tempered by his own battle with disease, “I like kids. They’re tough.”

So is Good, who combines painstaking laboratory work wiih gutsy speculations, or “probes,” much in ihe manner of a medical Marshall McLuhan. On one occasion, while treating a patient whose inability to resist infection coincided with the growth of a massive thymic tumor, Good began to speculate about the link between the thymus and agammaglobulinemia, a disease caused by a deficiency or lack of the major antibodies. He—together with others in his laboratories—conducted a series of experiments in which he removed the thymus from newborn rabbits. The results of the test—all of the animals failed to develop normal immune systems—led to recognition of the thymus’ role in the development of immunity.

Another example of Good’s intuitive flashes occured while he was working with Dr. Henry Kunkel at New York’s Rockefeller University in 1950. Good observed lhat patients with different types of tumors suffered from different types of infections. Those with Hodgkin’s disease, a cancer of the lymphoid system, were particularly susceptible to TB, fungus and viral infections; those with multiple myelomas, or cancers of the bone marrow, were vulnerable to such bacterial infections as streptococcus and pneumococcus. Subsequent observation and experiments at the University of Minnesota convinced Good that there were not one but two basic immune responses. One, controlled by the thymus, was responsible for delayed hypersensitivity, or certain types of allergic responses, and the rejection of foreign tissue. The other, involving blood-borne antibodies, helped the body to battle bacterial invaders.

Presented by Good and his group in the mid-’60s, the “two component” theory became the foundation of modern immunology, and led to new experiments and ways to understand the phenomenon of immune response. It also led to another of Good’s contributions —the first successful use of bone-marrow transplants to correct immunodeficiency disease.

Doctors had experimented with bone-marrow transplants in the mid-’50s, primarily to combat leukemia. But their efforts proved generally unsuccessful. Immunologically sound bone marrow contained cells that recognized the recipient of this gift as “foreign.” The new cells, in a phenomenon known as “graft v. host” reaction, thus rejected the host, producing lymphocytes capable of reacting with and destroying his tissue. In fact, the reaction, combined with infection and other factors, could prove fatal to the recipient whose immune system was either weak or absent.

Legacy. Good tried a different approach with five-month-old David Camp, who was suffering from hereditary immunodeficiency disease, which had already killed twelve infants on the maternal side of his family. Thinking back to work that he himself had done in 1956, Good remembered that mice given bone marrow from donors whose cells were genetically similar suffered from graft-v.-host reaction but never died from it. He reasoned that David, too, would survive if a good tissue match could be found.

Luckily, the infant had four sisters; one of them had cells similar to his. Using a local anesthetic, Good’s team inserted a needle into the bone of the sister’s leg and withdrew about a billion marrow cells. Then, they injected the cells into David’s peritoneal cavity, relying on the cells’ natural homing instincts to guide them to the bone marrow. The graft took. Graft-v.-host reaction set in, peaked and finally passed. The new cells overcame David’s lethal legacy by giving him the immune system he lacked; the child, now five, is immunologically normal.

Good’s accomplishments have made him a folk hero at home in Minnesota. He hopes to be equally productive at the Sloan-Kettering Institute, where he has already made administrative changes and, as one associate puts it, is “stirring up the reservation.” He is also expanding the scope of research at S.K.I., and has taken over an entire floor that he plans to staff with the best immunology researchers he can find at the institute or woo away from other hospitals and universities. The lab, he says, will study just about everything immunological —the immunodeficiency diseases that he calls “spontaneous experiments of nature”; allergies; and the relationship between aging and cancer.

Good’s most ambitious undertaking, however, will be a study that could make cancer immunotherapy a more exact science. At present, attempts to administer and evaluate the relatively new form of treatment are hampered by medicine’s lack of knowledge about the full nature and range of immune response. “What we need,” says Good, “is a workable system by which we can determine what is normal immunologically, a yardstick by which we can measure and evaluate immune response.” To arrive at that system, Good plans to run tests on every patient, employee and staff physician at S.K.I, and Memorial Sloan-Kettering Cancer Center, recording the various blood components, allergic reactions and response to common disease agents.

The result of such a study, involving thousands of people, says Good, will be a complete profile of the immune response, and a set of guidelines for those attempting to manipulate it to fight disease. “We know we’ve got a hell of a weapon in immunotherapy,” says Good. “This study will help us write the instruction manual so that we can use this weapon effectively.”

An early riser who can honestly echo Ernest Hemingway’s claim to have seen the sun rise every day of his life, Good is usually up by 4 and at his desk by 5 a.m. (he generally retires by 11 p.m.). He freely confesses to being a “work addict,” and concedes that his addiction may have contributed to the breakup of his first marriage. The marriage, by which Good has four children, ended in divorce in 1965. (He was remarried in 1967 to Joanne Finstad, a phylogeneticist—a specialist in evolutionary relationships—who worked with him in Minnesota.)

Theory. An ardent advocate of unhampered creativity, Good encourages his students and colleagues to try a wide variety of approaches in their search for answers. “Hypotheses,” he tells them, “are instruments. It doesn’t matter if they are right or wrong as long as they stimulate thought.” Thus, he reasons, no one need feel chagrined when his pet theory is shot down. “Right now, our theories are widely accepted,” says he, “but I’m sure that some young bastard will come along and make us mad as hell with some intellectual leap that postulates a completely new theory. Whether he’s right or wrong doesn’t matter. Just trying to find out if he is or isn’t should force us to think, to examine, to do new experiments. That’s what science is—or should be—all about.”

Good has detractors. Some find him too ambitious for their taste, viewing him as a scientific Sammy Click who occasionally lets his ego get in the way of his intellect. “He uses the pronoun we a bit too freely,” says one immunologist who feels that Good has taken credit for work done by members of his team. “He has a terrible ego drive and occasionally forgets what other people do,” says another, who is admittedly annoyed by Good and jealous of his ability to attract research funds and keep his name before the public.

But even Good’s severest critics acknowledge his accomplishments. “I’ll forgive Good any excess,” says a colleague and sometime competitor, “because he’s such an enormous stimulator of ideas. Even his bad papers have been well conceived.” Most agree and credit Good with being able to recognize an error and abandon it faster than anyone else in medical research. “Good never gets married to his hypotheses, so he doesn’t go through the pangs of divorce when one is proved wrong,” says a Minnesota associate. “He learns from everything and everyone.”

Good, who often acts as if he is running for the Nobel Prize, does not deny their charges. “Of course I’m an operator,” he admits. “I’m the most self-centered person in the world. I’ll use whatever there is to get things done the way I want them done.” At S.K.I., he says, “I hope I can be an effective operator when it comes to cancer.”

There is a good chance that he will be. Most researchers believe that the time is ripe for major discoveries in cancer research. Cancer, they believe, could be the first major killer to be controlled by immunological engineering.

Immunology has already led to the control of many serious illnesses. Immunological research resulted in the development of vaccines against polio, once a major crippler of children, and rubella, or German measles, which can cause serious birth defects in the children of women who contract it while pregnant. It has led to a broader understanding of allergies and an effective method of preventing erythroblastosis fetalis, a blood condition that can prove fatal to infants shortly after birth.

Hope for Lepers. Doctors can now use “transfer factor,” a substance first isolated from the white cells of blood by New York University’s Dr. H. Sherwood Lawrence in 1948, to transfer specific immune responses from a normal individual to another who has an immune system deficiency.

Drs. Martin Schulkind and Elia Ayoub of the College of Medicine of the University of Florida have used transfer factor to treat effectively chronic mucocutaneous candidiasis, a severe fungal infection of the skin and mucous membranes; others have used it successfully to treat agammaglobulinemia and Wiskott-Aldrich syndrome, a hereditary defect that leaves its victims unable to resist certain infections.

Immunology has even provided hope to victims of leprosy, one of man’s oldest and most dreaded diseases. Last month, Dr. Soo Duk Lim of Seoul National University, Korea, told an international workshop on immunodeficiency diseases at St. Petersburg, Fla., that he has used immunotherapy successfully on 14 patients with lepromatous leprosy, the most severe form of the disease. Lim, who worked closely with Good’s Minnesota group, infused the patients with large doses of white cells from unmatched donors weekly for periods of up to 16 weeks, in an attempt to stimulate an immune response against the bacillus responsible for the disease. The treatment, used on patients who had failed to respond to other therapy, helped in all cases, switching on idling immune systems. All patients are now disease free, and one has been so for a year and a half.

In addition to these dramatic results, doctors now know more than ever before about what happens in such autoimmune diseases as rheumatoid arthritis and systemic lupus erythematosus, in which the immune system goes haywire, recognizes certain of the body’s own tissues as foreign, and destroys them. They can also treat these illnesses with drugs that suppress the immune system, relieving the symptoms at the risk of leaving the body open to infection. But they have yet to learn the exact causes, let alone the cures for these diseases, which affect more than 5.5 million Americans.

There are other major mysteries to be solved in immunology. No one, for example, has figured out how to overcome completely the phenomenon of tissue rejection that plagues transplant surgery. Serum that inhibits the production and action of lymphocytes, the cells responsible for rejection, may cause severe reactions; immunosuppression, which is now the mainstay of transplant surgery, reduces the body’s ability to resist both infection and some cancer.

Research is now going forward to find the answers to these questions. Dr. William Hardy, an S.K.I, veterinarian, is conducting research in animal leukemias that could lead to better understanding of the disease in man. Dr. Philip Paterson and his colleagues at Northwestern University Medical School are trying to identify the viruses they believe are responsible for autoimmune diseases and develop specific agents to combat them. Scientists are seeking to improve existing techniques of tissue typing to facilitate transplants.

A former Minnesota researcher, meanwhile, has made a discovery that may well make tissue typing unnecessary. Dr. William Summerlin, now at S.K.I., has found that when skin is kept in tissue culture for several weeks, its antigens are somehow lost. As a result, the immune system of the patient can no longer recognize the donor’s skin as foreign. The skin can then be grafted onto any patient without being rejected. Summerlin’s work, which is still experimental, could eventually eliminate both the rejection problem and the need to match donor and recipient, enabling transplant surgeons to make wider use of organs taken from cadavers.

No one appreciates this potential more than Good, who sees immunology as the key to understanding—and ultimately controlling—almost all diseases that afflict man. “Understanding the immune system will enable us to do far more than treat allergies or immunodeficiency diseases, or to control cancer,” says Good. “It will enable us to understand the basic processes of life.” Good will not predict when this millennium will occur; immunologists are still groping for answers to questions that have puzzled scientists for centuries. But there is little doubt that they are groping in the right direction.