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Advances in immunotherapy for melanoma.

ABSTRACT: In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembrolizumab target programmed cell death protein 1 (PD-1) receptors and have proven to be superior to ipilimumab alone. The combination of ipilimumab and nivolumab has yielded higher response rates, greater tumor shrinkage, and longer progression-free survival than either monotherapy alone. As other promising immunotherapies for melanoma proceed through clinical trials, future goals include defining the role of immune checkpoint inhibitors as adjuvant therapy, identifying optimal combination strategies, and developing reliable predictive biomarkers to guide treatment selection for individual patients.

SUBMITTER: Redman JM

PROVIDER: S-EPMC4744430 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Advances in immunotherapy for melanoma.

Redman Jason M JM Gibney Geoffrey T GT Atkins Michael B MB

BMC medicine 20160206

In recent years, the introduction and Federal Drug Administration approval of immune checkpoint inhibitor antibodies has dramatically improved the clinical outcomes for patients with advanced melanoma. These antagonist monoclonal antibodies are capable of unleashing dormant or exhausted antitumor immunity, which has led to durable complete and partial responses in a large number of patients. Ipilimumab targets the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor. Nivolumab and pembr ...[more]

PMID: 26850630

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Project description:Paolo A Ascierto obtained his MD from the University of Naples, Italy, where he earned board certification in oncology. He is currently Director at the Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy Unit, National Tumor Institute 'Fondazione G. Pascale', Naples, Italy. Before his present position, he served consecutive positions there as a postdoctoral fellow and then as Vice Director of the Department of Clinical Immunology. His major research interests have included genetics and proteomics research of melanoma, apoptosis and cell death in human cancer and the assessment of molecular markers for tumor progression in melanoma, as well as the management of targeted therapies for melanoma, vaccination treatments and biochemical and immunological monitoring. He has served as a principal investigator in numerous clinical trials and has been widely published in peer-reviewed journals on topics related to his interests. Ascierto has been an invited speaker at more than 200 national and international meetings and is an active member of the Italian Society of Medical Oncology (AIOM), the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO), the European Organisation for Research and Treatment of Cancer (EORTC) and the International Society for Biological Therapy of Cancer (iSBTc). He is also the Editor-in-Chief of the Combination Strategies section of the Journal of Translational Medicine and serves as a scientific reviewer for several journals. James Larkin is a consultant medical oncologist specializing in the treatment of patients with cancer of the kidney and cancers of the skin, including melanoma. Larkin obtained a first-class degree in Natural Sciences from Cambridge University and undertook clinical training at Oxford University, qualifying in 1996. He underwent general medical training in London and, in 2001, won a Medical Research Council Fellowship for a Clinician, carrying out laboratory research at the Institute of Cancer Research (ICR), which led to the awarding of his PhD. He completed specialist training at The Royal Marsden Hospital and was appointed as a consultant in 2008. His research interests include the individualization of patient treatment in renal cancer and melanoma and the combination of novel targeted therapies for the treatment these diseases. He is the UK Chief Investigator for a number of clinical trials in melanoma and kidney cancer and has been awarded research grants from bodies including Cancer Research UK, the Wellcome Trust and the European Framework Programme 7. He is a member of the National Cancer Research Institute (NCRI) Melanoma Clinical Studies Group and Chair of both the NCRI Renal Cancer Clinical Studies Group and The Royal Marsden/ICR Committee for Clinical Research.

Project description:In 2011, two therapies were approved for the treatment of metastatic melanoma: ipilimumab, an immunotherapeutic agent, and vemurafenib, a BRAF kinase inhibitor. These approvals were based on data from phase III trials, which showed that treatment with these agents produced substantial improvements in overall survival (OS). Ipilimumab has been investigated in two phase III trials: one as monotherapy in patients with pretreated metastatic melanoma at a dose of 3 mg/kg and the second in combination with dacarbazine (DTIC) chemotherapy in patients with previously untreated metastatic melanoma at a dose of 10 mg/kg. Among the pretreated patients, ipilimumab monotherapy significantly improved median OS (Hazard ratio (HR): 0.66, P = 0.003) from 6.4 months in gp100 vaccine controls to 10.1 months. The rates of OS in the ipilimumab-alone group and the gp100 group, respectively, were 45.6% and 25.3% at 12 months and 23.5% and 13.7% at 24 months. In the second trial, OS was significantly longer in previously untreated patients receiving ipilimumab plus DTIC than those receiving DTIC plus placebo (11.2 months versus 9.1 months; HR: 0.72, P < 0.001), with higher survival rates in the ipilimumab plus DTIC group at 1 year (47.3% versus 36.3%), 2 years (28.5% versus 17.9%) and 3 years (20.8% versus 12.2%). When using ipilimumab in the clinic, special consideration should be given to immune-related adverse events (irAEs) and assessment of response. Established guidelines can be used to manage the majority of irAEs effectively. Proposed modifications made to the existing response criteria mean that the clinician can accurately detect immune-related responses that would have been considered representative of progressive disease using conventional criteria. Further research is warranted to establish how immunotherapeutic agents can be combined with conventional agents, with each other or with molecularly targeted agents such as vemurafenib, to further optimise clinical outcomes.

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Advances in immunotherapy for melanoma.

Publications

Advances in immunotherapy for melanoma.

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