How to Make Immunotherapy an Effective Therapeutic Choice for Uveal Melanoma.
Ontology highlight
ABSTRACT:
SUBMITTER: Marseglia M
PROVIDER: S-EPMC8122936 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Uveal melanoma (UM) is a rare cancer with a high mortality rate. In comparison to cutaneous melanoma, UM has unique immunological features. Arising in the immune suppressive environment of the eye, it maintains immune resistance once metastatic. This is considered a major obstacle for successful immunotherapy in UM. However, a growing body of evidence suggests strategies that may abrogate resistance and enhance antitumor immunity in UM. Recently, three new immune agents have been approved for melanoma. While these drugs demonstrate durable clinical responses with long-term remissions in metastatic cutaneous melanoma, only limited data exist in metastatic UM. In this review, immunological aspects of UM and data from clinical studies of immunotherapeutic agents and regimens for UM will be discussed.
| S-EPMC6094800 | biostudies-literature
Project description: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.
| S-EPMC10823941 | biostudies-literature
Project description:BackgroundUveal melanoma (UM) is a rare subtype of melanoma that generally has a poor prognosis once it has metastasized. Clinical trials evaluating immune checkpoint inhibitors (ICIs) in UM have demonstrated response rates lower than those seen in cutaneous melanoma. Despite lower efficacy demonstrated in initial ICI studies, there are a number of ongoing clinical trials investigating novel immunotherapy approaches in UM.SummaryThis review aims to summarize important ongoing clinical trials investigating immunotherapeutic approaches in UM and previous trials that have evaluated a number of immunologic interventions. A thorough clinical trial investigation was conducted through clinicaltrials.gov using the disease search terms "uveal melanoma" and "ocular melanoma," excluding non-immunotherapy-related trials. Here, we report on ICI, vaccine, adoptive T cells, and combination immunotherapy trials in UM.Key messagesThere is an increasing effort in the search for new, effective therapies for this difficult-to-treat disease, with immunotherapeutic approaches being of particular interest. Increasing knowledge of UM biology and development of new biomarkers will direct future drug development and trial design.
| S-EPMC8280448 | biostudies-literature
Project description:Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Compared to cutaneous melanoma (CM), which mainly harbors BRAF or NRAS mutations, UM predominantly harbors GNAQ or GNA11 mutations. Although primary UM can be controlled locally, approximately 50% of patients still develop metastases. To date, there have been no standard therapeutic strategies for the prevention or treatment of metastases. Unfortunately, chemotherapy and targeted therapies only induce minimal responses in patients with metastatic UM, with a median survival time of only 4-5 months after metastasis detection. Immunotherapy agents, such as immune checkpoint inhibitors, have achieved pioneering outcomes in CM but have shown limited effects in UM. Researchers have explored several feasible checkpoints to identify options for future therapies. Cancer vaccines have shown little in the way of therapeutic benefit in patients with UM, and there are few ongoing trials providing favorable evidence, but adoptive cell transfer-related therapies seem promising and deserve further investigation. More recently, the immune-mobilizing monoclonal T-cell receptor against the cancer molecule tebentafusp showed impressive antitumor effects. Meanwhile, oncolytic viruses and small molecule inhibitors have also gained ground. This review highlights recent progress in burgeoning treatments and provides innovative insights on feasible strategies for the treatment of UM.
| S-EPMC9264803 | biostudies-literature
Project description:ImportanceUveal melanoma (UM) is an intraocular primary malignant neoplasm that often gives rise to metastatic disease for which there are no effective therapies. A substantial proportion of UMs express the cancer-testis antigen PRAME (preferentially expressed antigen in melanoma), which can potentially be targeted by adoptive T-cell therapy.ObjectiveTo determine whether there may be a rationale for PRAME-directed T-cell therapy for metastatic UM.Design, setting, and participantsAn experimental study using a retrospective cohort of 64 patients with UM (median follow-up, 62 months) was conducted from January 8, 2015, to November 20, 2016, at the Leiden University Medical Center. Clinical, histopathologic, and genetic parameters were compared between 64 PRAME-positive and PRAME-negative UMs. HLA class I restricted, PRAME-specific T cells were stimulated with UM cell lines to measure their antigen-specific reactivity against these cell lines, which were analyzed for PRAME expression by real-time quantitative polymerase chain reaction. Uveal melanoma metastases from 16 unrelated patients were assessed for PRAME expression by messenger RNA fluorescence in situ hybridization and for HLA class I expression by immunofluorescence staining.Main outcomes and measuresInterferon γ production for antigen-specific reactivity and detection of PRAME and HLA class I expression in primary and metastatic UM.ResultsOf the 64 patients in the study (31 women and 33 men; mean [SD] age at the time of enucleation, 60.6 [15.6] years), PRAME expression was negative in 35 primary UMs and positive in 29 primary UMs. Positive PRAME expression was associated with a high largest basal diameter (15.0 vs 12.0 mm; P = .005), ciliary body involvement (59% vs 26%; P = .008), and amplification of chromosome 8q (66% vs 23%; P = .002). PRAME-specific T cells reacted against 4 of 7 UM cell lines, demonstrating that T-cell reactivity correlated with PRAME expression. Metastatic UM samples were positive for PRAME messenger RNA in 11 of 16 patients and for HLA class I in 10 of 16 patients, with 8 of 16 patients demonstrating coexpression of both PRAME and HLA class I.Conclusions and relevancePRAME is expressed in many primary and metastatic UMs, and about half of the metastatic UMs coexpress PRAME and HLA class I. The finding that PRAME-specific T cells in this study reacted against PRAME-positive UM cell lines suggests a potential role for PRAME-directed immunotherapy for selected patients with metastatic UM.
| S-EPMC5509351 | biostudies-literature
Project description:Uveal melanoma is a rare neoplasm with poor prognosis in the metastatic setting. Unlike cutaneous melanoma, treatment with kinase inhibitors or immune checkpoint inhibitors is not effective. Glycoprotein 100 (Gp-100) is a protein highly expressed in melanocytes and melanoma that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Tebentafusp targets tumor cells that express a peptide of Gp-100 presented by HLA*A0201, creating an immune synapse that kills targeted tumor cells. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. The aim of this comprehensive review is to summarize evidence of Gp-100 as a therapeutic target in melanoma, and the preclinical and clinical development of tebentafusp as a novel therapeutic strategy for patients with uveal melanoma.
| S-EPMC8656894 | biostudies-literature
Project description:Uveal melanoma (UM) is the most frequent ocular cancer in adults, accounting for ~5% of the total melanoma incidence. Although the primary tumor is well treatable, patients frequently develop metastases for which no curative therapy exists. Highly activated protein kinase C (PKC) is a common feature of UM and has shown potential as therapeutic intervention for UM patients. Unfortunately, PKC inhibition as single treatment appears to have only limited clinical benefit. Combining PKC inhibition with activation of p53, which is rarely mutated in UM, by MDM2 inhibitors has shown promising results in vitro and in vivo. However, clinical studies have shown strong adverse effects of MDM2 inhibition. Therefore, we investigated alternative approaches to achieve similar anticancer effects, but with potentially less adverse effects. We studied the potential of targeting MDMX, an essential p53 inhibitor during embryonal development but less universally expressed in adult tissues compared with MDM2. Therefore, targeting MDMX is predicted to have less adverse effects in patients. Depletion of MDMX, like the pharmacological activation of p53, inhibits the survival of UM cells, which is enhanced in combination with PKC inhibition. Also pan-PKC inhibitors elicit adverse effects in patients. As the PKC family consists of 10 different isoforms, it could be hypothesized that targeting a single PKC isoform would have less adverse effects compared with a pan-PKC inhibitor. Here we show that specifically depleting PKC? inhibits UM cell growth, which can be further enhanced by p53 reactivation. In conclusion, our data show that the synergistic effects of p53 activation by MDM2 inhibition and broad spectrum PKC inhibition on survival of UM cells can also largely be achieved by the presumably less toxic combination of depletion of MDMX and targeting a specific PKC isoform, PKC?.
| S-EPMC5874255 | biostudies-literature
Project description:Uveal Melanoma (UM) represents the most common primary intraocular malignant tumor in adults. Although it originates from melanocytes as cutaneous melanoma, it shows significant clinical and biological differences with the latter, including high resistance to immune therapy. Indeed, UM can evade immune surveillance via multiple mechanisms, such as the expression of inhibitory checkpoints (e.g., PD-L1, CD47, CD200) and the production of IDO-1 and soluble FasL, among others. More in-depth understanding of these mechanisms will suggest potential targets for the design of novel and more effective management strategies for UM patients.
| S-EPMC6848265 | biostudies-literature
Project description:Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Despite the efficient control of the primary tumor by radiation or surgery, up to 50% of patients subsequently develop metastasis, mainly in the liver. Once the tumor has spread from the eye, the treatment is challenging and the median survival is only nine months. UM represents an intriguing model of oncogenesis that is characterized by a relatively homogeneous histopathological architecture and a low burden of genetic alterations, in contrast to other melanomas. UM is driven by recurrent activating mutations in Gαq pathway, which are associated with a second mutation in BRCA1 associated protein 1 (BAP1), splicing factor 3b subunit 1 (SF3B1), or eukaryotic translation initiation factor 1A X-linked (EIF1AX), occurring in an almost mutually exclusive manner. The monosomy of chromosome 3 is also a recurrent feature that is associated with high metastatic risk. These events driving UM oncogenesis have been thoroughly investigated over the last decade. However, no efficient related therapeutic strategies are yet available and the metastatic disease remains mostly incurable. Here, we review current knowledge regarding the molecular biology and the genetics of uveal melanoma and highlight the related therapeutic applications and perspectives.
| S-EPMC6678734 | biostudies-literature
Project description:Uveal melanoma (UM) is characterized by relatively few, highly incident molecular alterations and their association with metastatic risk is deeply understood. Nevertheless, this knowledge has so far not led to innovative therapies for the successful treatment of UM metastases or for adjuvant therapy, leaving survival after diagnosis of metastatic UM almost unaltered in decades. The driver mutations of UM, mainly in the G-protein genes GNAQ and GNA11, activate the MAP-kinase pathway as well as the YAP/TAZ pathway. At present, there are no drugs that target the latter and this likely explains the failure of mitogen activated kinase kinase inhibitors. Immune checkpoint blockers, despite the game changing effect in cutaneous melanoma (CM), show only limited effects in UM probably because of the low mutational burden of 0.5 per megabase and the unavailability of antibodies targeting the main immune checkpoint active in UM. The highly pro-tumorigenic microenvironment of UM also contributes to therapy resistance. However, T-cell redirection by a soluble T-cell receptor that is fused to an anti-CD3 single-chain variable fragment, local, liver specific therapy, new immune checkpoint blockers, and YAP/TAZ specific drugs give new hope to repeating the success of innovative therapy obtained for CM.
| S-EPMC8616038 | biostudies-literature