At the turn of the century, one of medical science’s fondest dreams seemed tantalizingly close to realization. The dream was of a magic bullet, a merciful weapon that would seek out and destroy disease without harming the patient. No toxicity, no side effects--just a dead-sure shot that would penetrate to the heart of the affliction. The dreamer was the German Nobel laureate Paul Ehrlich, who in 1909, after seven years and 606 excruciating trial-and-error attempts, succeeded in chemically modifying arsenic to produce Salvarsan, the first effective antidote for syphilis. The achievement inspired in him the vision of a grand future in which even such seemingly unassailable afflictions as cancer would fall to the ingenuity of laboratory science. We no longer find ourselves lost on a boundless sea, he announced. We have already caught a distinct glimpse of the land which we hope, nay, which we expect, will yield rich treasures for biology and therapeutics.
Today it is all too clear that the dream has been deferred. While our arsenal of vaccines and drugs can prevent or cure a wide range of ills, cancer remains almost as intractable as ever. Cancer chemotherapy has undoubtedly saved lives--with surgery and radiation it is the standard treatment for the disease. But drugs that fight cancer behave more like buckshot than well-aimed bullets: they kill any rapidly dividing cell. And unfortunately, rapid cell division is the hallmark not only of cancer but also of certain normal, healthy cells, such as those in the lining of our gut, our hair cells, and the cells of our bone marrow and immune system. That is why chemotherapy is saddled with such miserable side effects: nausea, diarrhea, hair loss, anemia, an increased susceptibility to infections in general. With chemotherapy, the gamble is that the drugs will destroy the cancer before they destroy the patient. What we need--now as in Ehrlich’s day--are magic weapons that attack only cancer cells.
Thomas Waldmann thinks he may have one. Waldmann, the 62-year-old chief of the Metabolism Branch of the National Cancer Institute in Bethesda, Maryland, is head of a project to develop what might more accurately be called a magic missile than a bullet, a guided projectile that homes in on cancer cells more efficiently than an ICBM. I hate the military analogy, shrugs Waldmann, but it fits. These missiles are laboratory versions of our own natural weapons against disease--our antibodies.
Antibodies are tiny Y-shaped molecules produced by white blood cells called B cells, which patrol the bloodstream as part of the ever- vigilant immune system. When harmful foreigners--bacteria, viruses, or parasites--invade the body, B cells start churning out masses of antibodies, which then swarm over the interlopers, disabling them and marking them for destruction by the immune system’s killing cells. But not all antibodies go after all intruders. Rather, specific antibodies zero in on specific targets. It takes our B cell factories 10 to 14 days to build antibodies to a new invader (one reason that our immune response to a first-time infection is not instantaneous). After this first exposure, however, the capacity to rapidly churn out these antibodies stays with us. By the time we reach adulthood, it’s believed, most of us have antibodies that can recognize more than 100 million foreign molecules.
In the 1970s researchers began to dream of exploiting antibodies’ targeting skills. With the tools of modern cell biology at their disposal, scientists hoped to make antibodies that could zero in on objects of their choosing. If they succeeded, they could broaden the range of targets attacked by the immune system--extend it from obviously harmful foreign organisms to, for example, the hidden menace of cancer cells arising from within the body.
The breakthrough came in 1975. At the Medical Research Council Laboratories in Cambridge, England, Georges Köhler and César Milstein devised what is now the standard way of mass-producing such antibodies. First you inject a mouse with a specific target--call it protein X. This induces an immune response in the mouse, prodding some of its B cells to make antibodies to the foreign molecule. You then take a sample of the mouse’s B cells, including those making antibodies to protein X, and grow them in the lab. The trick is to fuse the antibody-making B cells, which are short-lived, with cancerous mouse B cells, which reproduce like crazy. This gives you a bunch of hybridomas, cells that not only spew out antibodies but also keep making copies of themselves--clones, in other words. You then pick a clone making the antibody you want and grow it in large numbers in lab dishes, giving you an inexhaustible supply of monoclonal (from a single clone) antibodies.
This technology was greeted with enormous enthusiasm, says Waldmann. It became clear one could use B cell factories like this to generate antibodies to a large array of things. Indeed, since the late 1970s monoclonal antibodies have been put to all sorts of uses other than the treatment of disease. For example, combined with a dye or radioactive label, monoclonals are a standard tool for tracking proteins in lab experiments. And they are used in screening tests for diseases as diverse as prostate cancer, AIDS, and hepatitis, as well as in at-home pregnancy tests.
Unfortunately, when it comes to actually combating disease, and cancer in particular, monoclonal antibodies have been a bitter disappointment. One 1988 survey concluded that clinical trials pitting monoclonals against cancer had produced only 23 partial and 3 complete remissions in 185 patients.
There were several reasons for these failures, according to Waldmann. The main one, he says, was that these monoclonal antibodies were not very good at killing. They were like smart missiles that knew where to go but didn’t know what to do when they got there. The upshot was that although monoclonals made a beeline for cancer cells, they neither killed the cells very effectively nor did a good job of enlisting the heavy guns of the immune system to help them out.
The antibodies weren’t discriminating enough, explains Waldmann. They were directed at virtually anything that differentiated a tumor cell from a normal cell, but not at anything critical to that particular tumor cell’s survival. Until researchers could find such a critical feature, Waldmann concluded, the missiles would be unable to stop a given cancer.
In 1979 Waldmann and his colleagues at the National Cancer Institute were studying a man suffering from cancer involving the white blood cells known as T cells. His was a rare but devastating disease called adult T cell leukemia, which on average kills within 20 weeks of diagnosis. Its cause was found to be a virus, now called HTLV-1. (In fact, it was in this very patient that virologist Robert Gallo identified HTLV-1 as the first known human retrovirus, a member of the family that now includes HIV, the AIDS virus.)
HTLV, the researchers learned, causes cancer by subverting the normal function of T cells. Normally when the body is threatened by infection, T cells are among the first immune cells to respond to the challenge. They secrete a protein known as a growth factor, in this case one called interleukin-2 (IL-2 for short), and display a receptor for it on their surface. When the growth factor locks onto the receptor, it stimulates the cells to multiply rapidly and go forth to fend off the invaders. Once the invaders are vanquished, however, the cells cease to make IL-2 and to put out receptors, and they return to a resting state.
But in this leukemia, says Waldmann, HTLV installs its genes inside the T cells’ DNA and permanently disrupts their function. It forces the cells to make the growth factor continuously and to keep the receptor for it on their surface. It’s a dangerous, unremitting, self-stimulatory cycle, says Waldmann, resulting in chaotic growth--in other words, cancer. Eventually there’s so much genetic damage that the cells don’t even need the prod of IL-2 to keep multiplying.
Could monoclonal antibodies, Waldmann wondered, be used to interfere with this insidious process? If you had an antibody that could stop the growth factor from seeing its receptor, prevent this critical relationship, you could starve the cell, he says. Then it would not only stop dividing, it would die.
Within two years, in 1981, Waldmann and his colleagues announced that they had produced a monoclonal antibody that targeted the IL-2 receptor on T cells. When loosed upon leukemia cells in lab dishes, these antibodies blocked the receptor, starving the cells of their IL-2 fix. What’s more, the antibodies went solely for cells displaying the receptor, leaving the healthy resting cells--the vast majority--untouched. Only a minute fraction of healthy cells, those actively growing in response to an infection, were ever likely to be vulnerable. Waldmann had found his target.
The first human tests took place between 1984 and 1990. Altogether Waldmann’s team treated 20 adult T cell leukemia patients, slowly dripping the antibodies into their veins over several treatment sessions. None of the 20 had side effects--an indication that the antibodies were indeed attacking only the diseased cells--and 7 of the patients went into remission, 3 of them complete. Today, three years after his treatment ended, one patient remains wholly free of disease.
It was a promising beginning, offering much more hope than earlier monoclonal trials. But we weren’t satisfied, recalls Waldmann. A number of the leukemic cells had gone beyond the stage where they could respond to this mouse monoclonal. Once the cells’ genetic damage was so great that they were able to multiply without IL-2, blocking the receptor did nothing. It was the same old problem: when it came down to it, monoclonal antibodies simply weren’t very adept at killing. They were guided missiles without a warhead. It was left to Waldmann to supply one.
We began to see the antibody not as a killer in itself, he says, but as a delivery system to bring in the killing agents. The agents were already at hand: anticancer drugs and radiation. Their problem was that in the process of destroying cancer cells, they destroyed healthy cells as well. With his antibody as a carrier, however, Waldmann hoped to deliver toxins and radiation directly to their destination, the cancer cells themselves.
Of the two approaches, Waldmann preferred radiation. Even with the strongest toxins, we’ve never been able to kill the tumor cells as effectively as we can with radiation, he says. Working with NCI inorganic chemist Otto Gansow, Waldmann succeeded in arming his antibody with a radiation source called yttrium 90. The virtue of yttrium 90 is that its radiation travels only a very short distance. You want the antibody and its payload to kill the cell that it sits on. But you don’t want it killing cells at a distance, he adds. That would be like giving whole body radiation from the inside rather than the outside.
You also don’t want the radioactive source to break loose from the antibody. If you release the yttrium by mistake, says Waldmann, the danger is that it could go to the bone and irradiate the bone marrow, giving you unacceptable toxicity. His solution: Equip the antibody with a chemical cage that holds on to its radioactive cargo until it has docked on the cancer cell. Once there, the antibody’s radiation penetrates to the cell’s nucleus, fracturing its DNA. Over the last two years the team has treated 15 people suffering from adult T cell leukemia with this souped-up missile. None had side effects, and 10 responded well: 8 went into partial remission, 2 enjoyed complete remission.
These results were even better than the first--but they were tempered by perhaps the biggest inherent problem facing monoclonal therapy. The monoclonals we’ve used so far are mouse proteins--foreigners to the human immune system, explains Waldmann. So our immune system responds to these monoclonals as if they’re a threat, by making its own antibodies against them. In other words, mouse monoclonals are limited in effect because our immune defenses promptly get rid of them. It may take a couple of weeks the first time around, but thereafter, in a healthy immune system, the rejection can be almost instantaneous. With some patients, recalls Waldmann, we had to give up treatment. As they got better, as their immune systems became stronger, they recognized the mouse antibody as foreign. Having devised a warhead-equipped missile, he must now disguise it. If you have a missile that is very obvious, it will be shot down, Waldmann says. But if you use a stealth missile . . .
Thus his latest project is making an antibody that can slip into the body undetected by our immune system. Working with molecular biologist Cary Queen of Protein Design Labs in Palo Alto, California, Waldmann’s team has used genetic engineering to make a humanized monoclonal that’s a little bit mouse and mostly human. They have snipped away the business end of the mouse antibody--the tips of its Y-shaped arms that actually seek out the IL-2 receptor--and spliced them onto a human antibody. The hope is that our immune system will consider this mongrel one of its own.
So far it looks as if the ruse will work. As a first step Waldmann tested the humanized antibody in macaque monkeys, whose immune defenses resemble our own. Whereas mouse antibody survived for a little over a day, humanized antibody lasted over four days, he says. In humans we anticipate it may last over ten days. Lab experiments also showed that the humanized monoclonal was better at enlisting the help of the immune system’s killer cells to polish off leukemic cells. But it remains to be seen just how well leukemia patients do when they’re given the humanized antibody.
Waldmann and others are also planning to test the range of this stealth missile. T cell leukemia isn’t the only disease that involves an overexpression of the IL-2 receptor. The same phenomenon occurs in other leukemias, lymphomas, and Hodgkin’s disease, as well as in malignant tumors of the head and neck and a type of lung cancer. It also occurs in noncancerous diseases resulting from a hyperactive immune response, such as autoimmune conditions and transplant rejections. Claudio Anasetti, an immunologist at the Fred Hutchinson Cancer Research Center in Seattle, is currently testing the humanized monoclonal in patients who have been given bone marrow transplants and who have developed a usually lethal type of graft-versus-host disease. (In these cases it’s the transplanted bone marrow that rejects its recipient by sending T cells to attack its new host.) Here, too, the antibody looks promising--it was not rejected and a single infusion prolonged the lives of 6 out of 12 patients.
Could Paul Ehrlich’s dream be realized one day, after all? In the war against cancer, hopes have too often been raised only to fall again, and Waldmann is too seasoned a veteran not to know it. Yet there’s no mistaking the thrill in his voice. These new, genetically engineered antibodies are a quantum leap beyond what was possible in the past, he says. You have to remember that only a few years ago there was nothing we could do for people with adult T cell leukemia. So when you see 10 out of 15 patients going into remission, that’s already very encouraging. No one hopes more fervently than Waldmann that his missile will continue to fly true.