Research Report: New Treatments for Melanoma

by Richard Saltus

As recently as five years ago, progress in treating life-threatening malignant melanoma was slow. Since then, several molecularly targeted drugs have burst on the scene, and new strategies for awakening the immune system to attack the cancer cells have yielded dramatic long-term survival benefits for some patients.

“The outlook for patients has never been so good – and we anticipate that in the next year or two it will be much better,” says Louise M. Perkins, PhD, chief science officer for the Melanoma Research Alliance, which funds research on the skin cancer.

In recent years scientists have tried cancer “vaccines” that stimulate a melanoma patient’s immune system to recognize the cancer cells as foreign and send T cells to attack them. These efforts had limited success, and researchers have turned to a new strategy – inhibiting the inhibitor. Instead of stirring up the cell-killing forces, the scientists would make antibodies that would block other molecules in the immune system that restrain or turn off an immune response to prevent an over-reaction.

Dr Stephen Hodi, director of the Melanoma Center at Dana-Farber Cancer Institute
Dr Stephen Hodi, director of the Melanoma Center at Dana-Farber Cancer Institute

One such antibody is called ipilimumab, approved by the Food and Drug Administration for treating advanced melanoma in 2011. Ipilimumab disables a molecular inhibitor called CTLA-4, which normally dampens the T cell immune response. With CTLA-4 inhibitory signal blocked, T cells can continue to attack and kill melanoma cells. Last September, F. Stephen Hodi, MD, director of the Melanoma Treatment Center at  Dana-Farber reported that about 20 percent of metastatic melanoma patients treated in research studies with ipilimumab were living as long as 10 years – a stunning result.

An even newer type of antibody, which evolved from years of research that began in the laboratory of Dana-Farber’s Gordon Freeman, PhD, and is exemplified by nivolumab, blocks the interaction between a molecule called PD-1 on immune T cells and another molecule, PD-L1, that melanoma cells often have on their surface. PD-L1 helps melanoma cells evade detection and attack by the immune system. In clinical trials, many patients who were given nivolumab to target PD-1 had their tumors shrink and achieved long-term responses. While more studies are needed, nivolumab may prove more effective than ipilimumab.

Even better results may come when these immunotherapies are combined with the new drugs that target BRAF, a common mutation in melanoma cells. Alexander Eggermont, a melanoma expert from the Netherlands, told a meeting in Boston recently, “Within the next five years, 50 percent of patients with metastatic melanoma may be ‘clinically cured’.”  By that, he means the therapies will maintain long-term control of the disease, even if it is not totally eliminated.

As exciting as the new wave of treatments is, prevention is the most effective means of combating melanoma. Public education focuses on avoiding excess ultraviolet exposure from the sun and artificial sources such as tanning beds. Monthly skin self-exams and awareness of the warning signs of melanoma may be helpful in finding most melanomas when they are at an early, curable stage.