Yvonne Saenger, MD
Assistant Professor, Medicine, Hematology and Medical Oncology
Assistant Professor, Dermatology
Icahn School of Medicine
at Mount Sinai The Tisch Cancer Institute
Melanoma care has fortunately undergone a whirlwind of changes over the past several years. Novel immunotherapies are perhaps the most exciting recent development in cancer care because patients can enjoy long-term benefit from these treatments, meaning that they are possibly “cured.” Thus, it is now considered possible to rid the body of cancer using immunotherapy in a significant fraction of patients with advanced melanoma. Immunotherapy can be very toxic, but it lacks the characteristic poisoning effects of chemotherapy and has the appeal of offering a more “natural” solution to cancer as it builds on the body’s own innate defense mechanisms to cause tumor rejection. Over the coming decades, the challenge will be to expand the minority currently curable with immunotherapy and also to introduce immunotherapies earlier in the disease course to prevent systemic spread in the first place.
In 1981, interleukin-2 became the first immunotherapy approved for treating patients with melanoma.
The drug reliably produces an approximate 15% response rate and a “cure” rate perhaps slightly below 5%. However, the mechanisms of action of interleukin-2 are largely unknown and skeptics of immunotherapy have remained unimpressed by the data for the drug. The key development that led to the real expansion of immunotherapy for melanoma was the observation that blockade of a negative regulator of T-cell activity, CTLA-4, could result in melanoma regression.
CTLA-4 is a protein expressed by T cells in response to activation, and it serves to dampen the immune response, thereby preventing autoimmunity. Thus, mice deficient in CTLA-4 develop widespread autoimmune disease. In this way, CTLA-4 serves to protect normal tissues against the immune system; however, it is sometimes used by cancer cells to hide from the immune system. By blocking CTLA-4, the tumor can be revealed as a foreign threat.
While the initial data for CTLA-4 blockade showed efficacy not far superior to interleukin-2, follow-up studies have shown impressive rates of survival following CTLA-4 therapy, with 4-year survival rates of approximately 40% in previously untreated patients treated with high-dose CTLA-4 blockade on clinical studies. These data suggest that, while most patients do not experience immediate tumor shrinkage, tumors may respond later in the treatment course, resulting in improved survival. The CTLA- 4–blocking antibody ipilimumab (Yervoy) was approved for the treatment of melanoma in March 2011.
The success of CTLA-4 blockade spurred further research, resulting in the discovery of a second clinical target, PD-1. PD-1, similar to CTLA-4, is expressed by activated T cells, and it appears to be induced by chronic inflammation. Similar to CTLA-4, PD-1 signaling leads to inactivity and sluggishness of T cells. Thus, CTLA-4 and PD-1 are described as “checkpoints” in immune activation. One way to describe the role of PD-1 is that the immune system might decide to tone down a prolonged immune response, as it appears unlikely that the foreign entity will be successfully eliminated and the attack becomes a waste of resources. Thus, PD-1 expression is high on T cells during chronic viral infections and in T cells infiltrating tumors.
Blockade of PD-1 has produced impressive responses in melanoma patients. In a phase I study, the PD-1 inhibitor pembrolizumab (MK-3475) had an overall response rate of 34%, and preliminary evidence suggests that these responses are durable.1
In another phase I study, combination therapy with the PD-1 inhibitor nivolumab and ipilimumab produced responses in 40% of patients.2 The latest data on pembrolizumab and nivolumab were presented in June at the 2014 ASCO Annual Meeting, and both drugs are expected to eventually be approved by the FDA.