Clinical predictors of survival in metastatic uveal melanoma

Lorenzo, Daniel; Piulats, Josep María; Ochoa, María; Arias, Luís; Gutiérrez, Cristina; Català, Jaume; Cobos, Estefanía; Garcia‐Bru, Pere; Dias, Bernardo; Padrón-Pérez, Noel; Caminal, Josep M.

doi:10.1007/s10384-019-00656-9

Cited by 43 publications

(39 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The antitumor activity observed for tebentafusp monotherapy (reduction in target tumor SLD and extended survival) in patients with mUM within this trial is promising for this rare cancer with high unmet medical need (26). Uveal melanoma arises from melanocytes within the uveal tract of the eye (27,28) and metastasizes in half of patients, with 90% of these patients developing metastases to the liver (17,29). mUM has a poor prognosis with 1-year survival rate of 10%-40% from development of metastases (30).…”

Section: Clin Cancer Res; 2020mentioning

confidence: 89%

Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma

Middleton

McAlpine

Woodcock

et al. 2020

Clinical Cancer Research

186

135

View full text Add to dashboard Cite

Purpose: Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T-cell receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100expressing tumor cells. Here, we report a multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp. Patients and Methods: Eighty-four patients with advanced melanoma received tebentafusp. Treatment efficacy, treatmentrelated adverse events, and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment. Results: Tebentafusp was generally well-tolerated and active in both patients with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. A 1-year overall survival rate of 65% was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNg pathway-related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating CXCR3 þ CD8 þ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash (likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) showed a positive association with patient survival. Conclusions: These data suggest that redirecting T cells using a gp100-targeting TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.

show abstract

Section: Clin Cancer Res; 2020mentioning

confidence: 89%

Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma

Middleton

McAlpine

Woodcock

et al. 2020

Clinical Cancer Research

186

135

View full text Add to dashboard Cite

show abstract

“…It is not known whether ocular treatment ever influences survival and, if so, in whom [15]. Metastatic spread occurs haematogenously and almost always involves the liver, with lung, bone and other organs less frequently affected [2,24]. Metastatic disease develops almost exclusively in patients who have tumours that show chromosome 3 deletion, BAP1 loss or a class 2 gene expression profile (as defined by expression of 12 genes that influence the metastatic spread) [25,26,27].…”

Section: Metastatic Diseasementioning

confidence: 99%

“…Almost 50% of patients with uveal melanoma (UM) develop metastatic disease (i.e., metastatic uveal melanoma (mUM)), despite successful treatment of the primary ocular tumour [1]. Metastatic disease usually involves the liver and is commonly fatal within a year of the onset of symptoms [2]. Systemic therapy for metastases rarely prolongs life [3]; however, recent clinical trials have shown encouraging results with tebentafusp (formerly IMCgp100), a first-in-class, bispecific, fusion protein that redirects CD3+ T cells to gp100-expressing melanoma cells, inducing cytolysis [4,5].…”

Section: Introductionmentioning

confidence: 99%

Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma

Damato

Dukes

Goodall

et al. 2019

Cancers

113

View full text Add to dashboard Cite

Metastatic disease from uveal melanoma occurs in almost 50% of patients suffering from this ocular tumour, with median survival from development of symptoms being around 1 year. In contrast to cutaneous melanoma, kinase inhibitors and immune checkpoint inhibitors are usually ineffective in patients with metastatic uveal melanoma. Tebentafusp is a novel form of immunotherapy based on the immune-mobilising monoclonal T cell receptor against cancer (ImmTAC) platform, which comprises a soluble T cell receptor that is fused to an anti-CD3 single-chain variable fragment. The T cell receptor domain of tebentafusp targets cells present a human leukocyte antigen-A*02:01 complexed with a peptide derived from the melanoma-associated antigen gp100, which is expressed strongly by melanoma cells, weakly by normal melanocytes and minimally by other tissues. The anti-CD3 domain recruits CD3+ T cells (and, indirectly, other immune cells), redirecting these to the melanoma cells. The most common adverse events with tebentafusp are manageable and usually transient. Early survival data in patients with metastatic uveal melanoma are promising when considered alongside historical data. Based on these encouraging results, a randomised study comparing tebentafusp to investigator’s choice of therapy in metastatic uveal melanoma is ongoing.

show abstract

“…Approximately 50% of patients with UVM develop metastatic disease (3), with the liver being the most common initial site of metastasis. Patients with metastatic disease are rarely candidates for curative surgery and generally have a poor prognosis; death often occurs within a few months of the development of metastases (4,5). Although the incidence rate of UVM is known to be influenced by a number of parameters, including demographic, geographic and, to a lesser extent, hereditary factors, little is known about the underlying mechanisms responsible for its initiation, progression or biological heterogeneity.…”

Section: Introductionmentioning

confidence: 99%

Fatty acid‑binding protein 5 predicts poor prognosis in patients with uveal melanoma

Yang

Zhang

et al. 2020

Oncol Lett

View full text Add to dashboard Cite

Fatty acid-binding protein 5 (FABP5), which participates in mediating the biological properties of tumor cells, has been recognized in several neoplasms. The present study aims to investigate FABP5 transcriptional expression profiles, reveal its underlying biological interaction networks and define its prognostic value in uveal melanoma (UVM). A total of 80 patients with UVM and their RNA-sequence data, available from The Cancer Genome Atlas (TCGA) database, was analyzed. A differential transcriptional expression profile was obtained from TCGA and the Oncomine databases. The survival benefits were analyzed using the Kaplan-Meier method and log-rank test. The correlation between FABP5 expression and immune infiltration level was analyzed using the Tumor Immune Estimation Resource database. Functional enrichment analyses using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and signaling hallmarks were utilized to describe the biological process, molecular functions, cellular component and significantly involved pathways. The elevated transcriptional expression of FABP5 was significantly associated with shorter overall survival (OS) and worse progression-free survival (PFS) times in patients with UVM (P<0.001). Moreover, FABP5 expression was significantly and positively correlated with tumor purity and CD8 + T cells and was negatively correlated with the infiltrating levels of CD4 + T cells and neutrophils. Gene Set Enrichment Analysis was performed to obtain 100 significantly associated genes of FABP5 and FABP5 was found to be critical in several hallmark pathways, including allograft rejection, complement, interleukin-6/Janus kinase-STAT3 signaling, interferon γ response, inflammatory response and tumor necrosis factor α signaling via NFκB. The present study is the first to demonstrate that FABP5 expression was positively associated with progression-associated clinicopathological factors and poor prognosis in UVM, which suggests its likely function as an oncogene and prognostic marker in patients with UVM.

show abstract

Clinical predictors of survival in metastatic uveal melanoma

Cited by 43 publications

References 44 publications

Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma

Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma

Tebentafusp: T Cell Redirection for the Treatment of Metastatic Uveal Melanoma

Fatty acid‑binding protein 5 predicts poor prognosis in patients with uveal melanoma

Contact Info

Product

Resources

About