News & Press
Meet Dr. Weber: Melanoma Researcher
Guest blog post by Jeffrey Weber, MD, PhD, deputy director of the Perlmutter Cancer Center and codirector of the Melanoma Research Program at NYU Langone Health. Learn more about melanoma from Dr. Weber in a series of animated patient videos.
Immunotherapy for cancer, and specifically for melanoma, was pursued for decades with limited success until the 1990s, when laboratory researchers discovered that the function of T cells is controlled by checkpoint proteins. Blocking these proteins with engineered antibodies to alter their anti-tumor effectiveness was a turning point in the development of new therapies, in which melanoma led the way as the poster child for development of checkpoint inhibitor antibodies. Antibody therapy moved into the clinic and today, there are 4 approved by the FDA for melanoma: ipilimumab (Yervoy) blocks a checkpoint protein called CTLA-4; pembrolizumab (Keytruda) and nivolumab (Opdivo) block the checkpoint protein called PD-1; and atezolizumab (Tecentriq) blocks PD-L1.
The first antibody, ipilimumab, was tested in patients with advanced melanoma, resulting in long term survival for patients that previously would have lived less than a year. For the first time, we began to contemplate curing patients with this deadly disease. Trials with ipilimumab led to its FDA approval in 2011 for advanced disease, after which it was felt to be safe to test it in earlier stage disease as adjuvant therapy after surgical removal of early stage melanoma at high risk for relapse. Early trials performed by us showed promise, culminating in the first international randomized adjuvant trial, EORTC 18071, which also showed a survival benefit for patients with melanoma and was reviewed and approved by the FDA in 2015. Subsequently, a large randomized trial comparing the checkpoint inhibitor nivolumab to ipilimumab showed that nivolumab had clear increased benefit compared to ipilimumab. Nivolumab rapidly became a new standard of care treatment for patients after surgical resection of melanoma which led to its approval in the adjuvant setting by the FDA in 2017.
Although single agent checkpoint inhibitors are approved in metastatic melanoma, the combination of ipilimumab and nivolumab is the regimen that provides the longest survival yet seen in patients with metastatic melanoma, but this regimen is handicapped by significant toxicities. Looking forward with new research designs to improve treatment options, we are conducting trials that test whether the addition of a third drug to this doublet can either increase the benefit or reduce the toxicity that it causes. An ongoing trial of ipilimumab with nivolumab and an antibody that blocks the IL-6 receptor called tocilizumab is evaluating the possibility that we can reduce the side effects seen with combination immunotherapy in metastatic melanoma. Additionally, current adjuvant trials will assess whether the addition of a neo-antigen vaccine augments the impact of adjuvant PD-1 blockade, and whether new drugs like NKTR 214 can do the same.
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