A Wider Vision For Treating Melanoma

Researchers look for tests and therapies that could change outcomes

New therapies for melanoma patients can improve survival. Unfortunately, these therapies only provide durable responses in a subset of patients, because most tumors develop resistance to the treatment and eventually progress, says Iman Osman, MD, associate director of emerging programs and education and director of the Interdisciplinary Melanoma Cooperative Group, both at the Laura and Isaac Perlmutter Cancer Center at NYU Langone.

“Age has not been sufficiently studied as a factor,”states Iman Osman, MD.

The Interdisciplinary Melanoma Cooperative Group research team has been looking for ways to predict which patients will respond best to which treatments—and to find new treatment targets to help those not benefitting from current therapies. Some of the team’s findings, reported at the 2014 meeting of the American Society of Clinical Oncology (ASCO) in Chicago, suggest promising avenues related to pa- tients’ immune responses to melanoma.

One such study from Dr. Osman’s team suggests that aging leads to decreased immune response, and that decrease might be contributing to the worse prognoses of melanoma patients age 60 and older. These older patients have proven to be at higher risk for a worse outcome than younger patients regardless of tumor thickness or staging, according to Dr. Osman, a professor in the departments of dermatology, medicine, and urology at NYU Langone.

To see if the older patients had a more limited response than younger patients to melanoma immunotherapies given after surgical removal of the tumor, the team looked at more than 300 prospectively enrolled, stage III melanoma patients at NYU Langone. The cohort was about evenly divided between those younger and older than age 60, and patients were followed for a median of 45 months.The older patients had shorter overall survival, explained Nathaniel H. Fleming, a research associate in the Interdisciplinary Melanoma Cooperative Group.

Melanoma cells Dr. Osman clarified that this survival difference was mostly due to differences among the patients receiving immunotherapies given at the time patients were enrolled. “When the older patients received vaccines or interferon in our study, they didn’t do as well in terms of survival as younger patients,” says Dr. Osman. She also noted that the data cannot be extended nor made generalizable to the newer, more effective immunotherapies (e.g., anti-CTLA-4 and anti-PD-1), which are currently under study.

Another key finding in the older melanoma patients was the lack of tumor-infiltrating lymphocytes (TILs)—a sign of an impaired immune system. “We found 35 percent of older patients had no TILs in their tumors, compared with 21 percent of the younger patients,” observed Mr. Fleming. Older patients were also less likely than younger patients to have BRAF gene mutations, which can be targeted using the new melanoma drugs, vemurafenib (Zelboraf®) and dabrafenib (Tafinlar®). In the study cohort, 40 percent of older patients had BRAF mutations, versus 63 percent of younger patients.

Dr. Osman contends that age has not been sufficiently studied as a factor in cancer outcomes. “Our data suggest that in analysis of randomized controlled trials, age needs to be considered as a confounding factor,” she says.

“We might be able to change the way we treat melanoma,”says Dr. Silva.

In another study, Dr. Osman’s team found a different factor that may be related to melanoma progression and recurrence, at any age: the impairing of T-cells and “natural killer” (NK) cells, which are important to the immune system’s ability to combat melanoma cells. “In some patients the T-cells and NK cells were ‘exhausted,’” says Ines Pires da Silva, MD, a clinical research fellow in the melanoma program with a special interest in immunology. “These cells are less functional, and consequently, they proliferate less, they produce less cytokines and they’re less cytotoxic—they can’t kill tumor cells,” she add- ed. NK cells with lower cytotoxic ability were also associated with local and distant metastases.

Dr. Silva and the study team speculate that melanoma may release cytokines or other soluble molecules that can induce exhaustion of NK cells. NK exhaustion appears to begin gradually in the early stages of melanoma, but to learn more about that progression the team has been phenotyping NK cells in the blood of melanoma patients in all stages of the disease and examining the role of these cells in disease progression.

According to the research team, the work so far suggests that targeting exhaustion markers in NK cells early in melanoma progression could present a new therapeutic strategy. Some exhaustion markers are already among the targets of new melanoma immunotherapies. These include CTLA-4, which normally suppresses T-cell function and is blocked by the drug ipilimumab (Yervoy®), and PD-1, which is inhibited by nivolumab and lambrolizumab, currently in clinical trials.

Drs. Osman and Silva have also been working on a pilot project to study multiple gene mutations in tumors, research that they hope will guide treatment decisions. The project identifies active mutations in melanoma patients using a clinical assay that encompasses targeted sequencing of 50 genes with known impact on tumor progression. “By looking be- yond the most common mutated genes in melanoma,” says Dr. Silva, “we can find new targetable mutations and change the way we treat the disease.”