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Uveal melanoma: Recent advances in immunotherapy.

ABSTRACT: Uveal melanoma (UM) is the most common primary intraocular cancer in adults. The incidence in Europe and the United States is 6-7 per million population per year. Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection, up to 50% of UM patients develop metastases that usually involve the liver and are fatal within 1 year. To date, chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM, which is still characterized by poor prognosis. No standard therapeutic approaches for its prevention or treatment have been established. The application of immunotherapy agents, such as immune checkpoint inhibitors that are effective in cutaneous melanoma, has shown limited effects in the treatment of ocular disease. This is due to UM's distinct genetics, natural history, and complex interaction with the immune system. Unlike cutaneous melanomas characterized mainly by BRAF or NRAS mutations, UMs are usually triggered by a mutation in GNAQ or GNA11. As a result, more effective immunotherapeutic approaches, such as cancer vaccines, adoptive cell transfer, and other new molecules are currently being studied. In this review, we examine novel immunotherapeutic strategies in clinical and preclinical studies and highlight the latest insight in immunotherapy and the development of tailored treatment of UM.

SUBMITTER: Sorrentino FS

PROVIDER: S-EPMC10823941 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Uveal melanoma: Recent advances in immunotherapy.

Sorrentino Francesco Saverio FS De Rosa Francesco F Di Terlizzi Patrick P Toneatto Giacomo G Gabai Andrea A Finocchio Lucia L Salati Carlo C Spadea Leopoldo L Zeppieri Marco M

World journal of clinical oncology 20240101 1

Uveal melanoma (UM) is the most common primary intraocular cancer in adults. The incidence in Europe and the United States is 6-7 per million population per year. Although most primary UMs can be successfully treated and locally controlled by irradiation therapy or local tumor resection, up to 50% of UM patients develop metastases that usually involve the liver and are fatal within 1 year. To date, chemotherapy and targeted treatments only obtain minimal responses in patients with metastatic UM, ...[more]

PMID: 38292657

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Project description:Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.

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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Uveal melanoma: Recent advances in immunotherapy.

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Uveal melanoma: Recent advances in immunotherapy.

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