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Invoking an immune system response // Targeting cancer-causing genetic mutations // or a combination of the two?

Melanoma: Saving Our Skin

By Cathryn Delude // Photographs by Christian Chaize // Winter 2011
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beach, Lagos

Christian Chaize

A diagnosis of melanoma is very bad news: Millimeter per millimeter of tumor, it’s among the deadliest cancers. Typically first appearing as a dark, irregular skin lesion, it can spread rapidly to every organ. There are some 68,000 new cases of melanoma in the United States each year, and the incidence is growing, despite warnings to stay out of the sun or wear sunblock to minimize exposure to ultraviolet radiation, the disease’s most important risk factor. Highly curable if found early, melanoma grows aggressively if undetected. Nationwide the cancer kills almost 9,000 people a year, mostly those with fair skin, often in the prime of life and frequently within mere months of discovering that their cancer has metastasized far and wide.

The best hope is a harrowing treatment for which only the fittest patients qualify: intensive immunotherapy that uses high doses of interleukin-2 (IL-2), a potent immune hormone. IL-2 therapy requires multiple hospital stays, during which patients receive intravenous infusions several times a day. The catalogue of side effects includes a racing heart, flulike chills, decreased blood pressure, vomiting and diarrhea, and edema, which can cause 10 to 20 pounds of weight gain.

Even then, no more than 20% of patients who get the treatment benefit, though 6% appear cured for life. Still, immunotherapy is better than the only other Food and Drug Administration-approved treatment for advanced melanoma: Chemotherapy with dacarbazine gets only a 10% response rate, and patients survive an average of just seven months.

The idea of harnessing the body’s immune system to defeat malignancies has long had appeal, and perhaps because of the dearth of other effective treatments, research on the disease has always skewed toward immunotherapy—more so than for other cancers. But beyond that, some scientists speculate that melanoma is particularly immunogenic, producing antigens that immune cells can recognize as dangerous. There have also been rumors of advanced melanoma spontaneously regressing, as if the immune system can sometimes clear the cancer on its own and just needs to be encouraged. But many physicians are skeptical about such medical miracles. “I’m still waiting to see my first case,” says Paul B. Chapman, a melanoma researcher at Memorial Sloan-Kettering Cancer Center in New York City.

Chapman thinks it’s likely that there has been more focus on immunotherapy for melanoma simply because melanoma cells, compared with those of other cancers, are easier to grow and study, so scientists have learned more about melanoma’s antigens. An added encouragement has been that researchers have witnessed more—if still very few—responses in melanoma than in other cancers to strategies that rev up the immune response of killer T cells.

Whatever the reason, the field has invested a good share of research dollars in immunotherapy. But rewards have been scant: Beyond interleukin-2’s limited effectiveness, a cancer vaccine called gp100, now in clinical trials, has so far extended survival no longer than dacarbazine does. Perhaps some of the money and effort would have been better spent on a different approach—such as developing targeted therapies that inhibit one of the mutated genetic growth signals on which cancer cells depend. Yet although that approach has worked for rare cancers driven by just one mutation, such an aggressive, invasive cancer as melanoma has seemed likely to involve many mutations.

Now, though, almost simultaneously, scientists in both the immunotherapy and the targeted therapy camps have achieved breakthroughs they describe as unprecedented. A new form of immunotherapy called ipilimumab (researchers refer to it as Ipi) targets immune cells instead of cancer cells, and it’s the first drug to prolong survival in metastatic melanoma, even if it doesn’t always shrink tumors. The other new treatment, known as PLX4032, is a targeted therapy that inhibits a particular cellular growth signal, and it has shrunk tumors more dramatically than previous approaches have.

Each therapy could receive FDA approval within a year, and there are already plans for trials testing them in combination as well as to fight other cancers. “For those of us treating a disease that we’ve had very little success against in more than 30 years,” says Steven O’Day, director of the melanoma program at the Angeles Clinic & Research Institute in Santa Monica, Calif., “the excitement is palpable.”

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Melanin: Our Natural Shade

Researchers are at work on a cream that would confer the beneficial effects of a tan yet shield us from the risks of the sun’s dangerous ultraviolet rays.


1. “Inhibition of Mutated, Activated BRAF in Metastatic Melanoma,” by Keith T. Flaherty et al., The New England Journal of Medicine, Aug. 26, 2010. The authors report the promising (albeit early) outcome of the first clinical trial for metastatic melanoma using a targeted therapy: a BRAF inhibitor (PLX4032) that silences an oncogenic mutation present in three-fifths of patients.

2. “Improved Survival With Ipilimumab in Patients With Metastatic Melanoma,” by F. Stephen Hodi et al., The New England Journal of Medicine, Aug. 19, 2010. Results of a Phase III trial of a new form of immunotherapy that uses an antibody to disable a “brake” in immune cells, freeing them to fight cancer cells.

3. “Ipilimumab: Controversies in Its Development, Utility and Autoimmune Adverse Events,” by Jeffrey Weber, Cancer Immunology Immunotherapy, May 2009. Weber suggests that the slower but more durable response of patients to ipilimumab than to chemotherapies or targeted therapies may justify a new criterion for deeming immunotherapy a success or a failure.

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