Medicine: Fighting Melanoma
Doctors at the Hadassah–Hebrew University Medical Center are developing an innovative vaccine that will help identify and destroy skin cancer.
The ugly black lesion on your skin has been cut away, and you have started to put behind you the whole nightmare of this most virulent of cancers. You are one of the lucky ones. And then….
“In one in every three melanoma patients, the disease is metastatic,” says Dr. Michal Lotem, oncologist, dermatologist and senior physician at the Sharett Institute of Oncology at the Hadassah–Hebrew University Medical Center at Ein Kerem. “In these patients, it recurs after it’s been excised, either in the form of another skin lesion or as a tumor on a lymph node, or in the lungs or brain.”
These secondary metastatic tumors are far harder to eradicate than primary growths and are minimally responsive to chemotherapy and radiotherapy. Only one in five of their victims survives beyond five years. Researchers, therefore, are looking for new ways to fight off this highly aggressive, fast-growing and increasingly common cancer that can, at worst, kill within a week. A vaccine, under development for some 15 years, is one of the most promising; Hadassah is among a half-dozen centers worldwide at the forefront of its creation.
“We were recruited to this vaccine-research effort by the Hipple Cancer Center [now the Cancer Prevention Institute] of Dayton, Ohio, in 1996,” says Dr. Tamar Peretz, head of oncology at Hadassah. “We’re involved both in clinical trials of the vaccine and in basic research. One research direction is an ambitious protocol involving the immune system, shared with us by immunotherapy pioneer Steven A. Rosenberg, head of tumor immunology at the Center for Cancer Research in the United States.”
Hadassah’s prominence in efforts to develop a vaccine is a blend of its research expertise and the large number of melanoma cases it sees. Some 200 newly diagnosed patients register at the medical center’s melanoma clinic each year—about one in five of Israel’s melanoma victims.
The incidence of melanoma in Israel has leapt in the past decade, as it has worldwide, from 750 new cases a year to 1,100. The primary reason is sun exposure.
“Melanoma is a cancer of the skin’s pigment-producing cells, its melanocytes, that give skin its color and protect its deeper layers from the sun’s ultraviolet rays,” says Dr. Lotem. “Pigment is our built-in sunscreen. The more we have, the better we’re protected from the UV rays that can turn the melanocytes cancerous. In a country like Israel, where there’s a lot of sun and many fair-skinned people, you unfortunately see a lot of melanoma.”
What power, then, can a vaccine have against the sun? “Melanoma is an immunogenic cancer,” explains Dr. Lotem. “That is, its own constituents can evoke an immune response. In fact, in 10 percent of patients, the primary melanoma tumor will disappear forever without any treatment, defeated by the patient’s own immune system.”
The immune system has the power to defeat cancer, yet it rarely even enters the fight. “Cancer outwits the immune system by creeping under its radar,” says Dr. Lotem. “Because malignant cells derive from normal cells, they’re part of ‘self’ gone wrong, and the immune system fails to identify them as enemy, leaving them to reproduce endlessly and destroy their host.”
The cancer vaccine aims to “teach” the patient’s immune system to recognize certain molecules contained only by tumor cells and unleash the body’s deadly immune response against them.
“The vaccine we’re developing is therapeutic, designed to stimulate a strong immune response to metastatic melanoma,” says Dr. Lotem. “Its job is to alert the immune system, break its tolerance of the cancer and so increase resistance to the disease. This is in contrast to vaccines like those for measles and smallpox, whose job is to prevent the disease altogether.”
To teach the immune system to recognize melanoma, it must learn the individual fingerprint of the cancer. The patient’s own tumor cells form the basis of the vaccine, meaning that each vaccine must be custom designed.
The ideal candidate for the melanoma vaccine is a patient who has had a large metastatic melanoma tumor removed and is, for the moment, disease free. The vaccine process starts when the freshly removed tumor is dispatched to Hadassah’s laboratory, where whole melanoma cells are extracted, coated and irradiated to the point where they are still alive but can grow no further. This shows the immune system the enemy. Proteins called cytokines, which boost the growth of the immune system’s killer cells, are then mixed in. The resulting serum is administered in a series of eight monthly injections following low-dose chemo-therapy that jump-starts breakdown of the body’s tolerance of cancer cells. Hadassah currently holds the treated melanoma cells of more than 400 high-risk patients from all over the country, keeping them as a kind of private bank deposit for each.
“I was really happy to take the vaccine,” says a 34-year-old Tel Aviv woman, whose melanoma began on her lower legs. The woman, who preferred not to give her name, is one of 250 patients who have received the vaccine at Hadassah. “There were no side effects from the shots, so my life went on as usual. But more than that, I felt I was helping my body fight off the disease in a healthy way, not…throwing poisons into it like in chemotherapy. It’s three years since I completed the vaccinations, and I’m still thankfully clear of disease.”
In about 50 percent of vaccinated patients, the disease will not recur. “The figures aren’t yet good enough,” notes Dr. Lotem, “but they more than double the 20 percent who escape recurrence without vaccination.
“Because of the one-in-two success rate,” she adds, “the vaccine should be seen as a platform or starting point to be combined with other strategies.”
One additional strategy now being researched is an agent that modifies the immune system. “It’s been developed by an international pharmaceutical company, which approached us for clinical trials,” says Dr. Lotem. “We’ve used it together with the vaccine in 20 patients so far, and the results have been very encouraging—beyond expectations.”
The Hadassah team is also investigating how well the vaccine works in less-than-ideal candidates. “When we use a modality in oncology, it’s best to be realistic,” explains Dr. Lotem. “A mild treatment [like the vaccine] won’t usually work against massive disease.”
But even in patients in whom only part of a tumor can be surgically removed, the team has seen that adding the vaccine to other immunomodifiers can make the cancer regress. This is especially exciting, according to Dr. Lotem, because it is rare for a non-toxic immunomodifier to achieve this. One patient in whom this unexpectedly happened is a man in his early sixties.
“He came to us with a deadly variant of melanoma—a tumor in his eyeball and a spread to his liver,” she says. “He was a warm, intelligent man who never complained, was surrounded by loving family and had a very poor chance of survival.”
The man had surgery and underwent chemotherapy. “It seemed unlikely the vaccine would help, but we gave him that as well, together with the immunomodulator interleukin-2,” says Dr. Lotem. “Six months later, his eye and liver are miraculously clear of disease. We believe this combination activated his immune system, which we pray will continue to defend him against a small malignant lesion that’s now appeared in his bone.”
This, however, is largely uncharted territory. While Dr. Lotem and her colleagues believe that an effective melanoma vaccine will lead the way to vaccines against other forms of cancer, research is not yet there.
“Lymphoma, colon and renal carcinoma, which are all immunogenic cancers like melanoma, will probably be among the next to target,” she says. “We’ve tried our vaccine in some kidney and colon cancer patients, but have conducted no large-scale study as yet because of limited resources.”
Meanwhile, even as they forge ahead with the melanoma vaccine, Hadassah’s oncologists are investigating other ways to manipulate the immune system. Dr. Rosenberg’s protocol, still at laboratory stage, is one in which they are investing significant research energy. “The aim is to boost the immune systems of cancer patients by taking out a few of their immune system cells, multiplying and strengthening them and returning them to the patient,” says Dr. Lotem.
As a dermatologist and an oncologist, Dr. Lotem treats melanoma patients from detection onward.
“Many patients are with me for years,” she says. “I see them through the stress and fear of diagnosis, therapy and follow-up. When they respond to treatment, the fear begins to subside, but with every follow-up scan, they’re taut with tension again. When they come for their results, their eyes rake me for clues about whether the news is good or bad It’s wonderful when I can immediately say to them: ‘The scan was fine!’ When I cannot say it was fine, it’s terrible. That’s why the research is so central for me.
“I’m waiting for the day when,” she adds, “if I have bad news to give a patient, I can balance it with the good news of a simple treatment that produces a permanent cure.”