A breakthrough in the activation of the immune system against metastatic melanoma

An article by Dr. Michal Lotem, Director of the Center for Melanoma and Cancer Immunotherapy at the Sharett Oncology Institute, Hadassah Ein-Kerem Medical Center

Metastatic melanoma is an aggressive disease that carries a difficult prognosis - a significant number of patients do not survive more than a year after diagnosis. Every year, about 850 new cases of invasive melanoma are diagnosed in Israel, about 200 patients are diagnosed in the metastatic stage, in which the median survival time can vary between 6-9 months.
Two new drugs recently approved for use by the FDA for the treatment of advanced melanoma constitute a revolution in the field of treatment of the disease, and defined the year 2011 as the year of melanoma. These are the first drugs in 13 years to be registered by the US Food and Drug Administration to treat the disease.

From the 70s of the last century, efforts were devoted to harnessing the immune system to act against cancer, with a mindset similar to that used in infectious diseases. But a cancerous tumor is not perceived by the body's systems as an invader or a foreigner, and in most cases a tolerance to it develops. More than one mechanism in the human body contributes to the resistance of cancer. Two treatments that activate the immune system were previously used in melanoma, one, interferon alpha - as a preventive treatment for melanoma patients at high risk of disease recurrence, and interleukin-2 for the treatment of metastatic melanoma. Despite some effectiveness, the response rates to drugs are low and the side effects are numerous.

The therapeutic horizons in melanoma expanded this year, when the US Food and Drug Administration (FDA) approved YERVOY for the treatment of metastatic malignant melanoma. It is a monoclonal antibody called
anti CTLA-4, which blocks a receptor on immune system cells (T lymphocytes). This receptor normally inhibits the activity of the immune system. The drug prevents the receptor from its inhibitory effect, and thus releases the inhibition from the T cells. Freed from inhibitions, the immune system begins to act on its own in an increased manner against the cancer tumor, and the lymphocytes activate their killing mechanisms to eliminate the cancer tissue. The side effects of the drug also originate from the vigorous activation of the immune system. They include colitis, rashes and disorders of the endocrine glands. Most of the side effects can be overcome by using steroids. It is interesting to note that often patients who experienced side effects responded better in terms of the regression of their tumor.
YERVOY has shown in large controlled studies a significant extension of life in metastatic melanoma patients, the improvement in survival is evident even after one or two years, and in some patients treatment with the drug even allows patients to live for more than three years with a good quality of life.

The breakthrough in treatment inspires hope especially in Israel, which faces a high percentage of melanoma cases, which is increasing year by year, and affects all adult age groups, from the age of 20 onwards.
YERVOY was approved following the results of a clinical study, which was published in the New England Journal of Medicine, in which the standard treatment for metastatic melanoma was compared to the combined administration of the same treatment together with the new anti-CTLA4 antibody. The study included 502 patients suffering from metastatic melanoma and it was found that at the end of the first year of follow-up, 47.3% of the patients with the combination containing YERVOY survived, compared to only 36.3% among those treated with the standard treatment alone. At the end of two years, the ratio of survivors was 28.5% compared to 17.9%, and at the end of three years, 20.8% of the patients in the combined treatment with YERVOY survived, compared to only 12.2% among those treated only with the standard treatment. At the end of the study it was found that treatment combining YERVOY reduced the patient's risk of dying from his disease by 72%. The special thing about YERVOY treatment is that the drug is given over a period of 9 weeks, after which the patient is under observation, but without active treatment. In patients in whom disease regression was observed, the response persisted for many months, often without the need for further treatment. In some patients the response is very prolonged, and lasts for years.

YERVOY marks a new chapter in harnessing the immune system against melanoma in particular and cancer in general. In the future, new combinations will be tested, the aim of which is to further increase the effectiveness of the drug, for example a combination with the administration of anti-cancer ingredients, or a combination with Zalboraf, another new drug registered for melanoma.