Immunotherapy for uveal melanoma.
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ABSTRACT:
SUBMITTER: Kim DW
PROVIDER: S-EPMC6094800 | biostudies-literature | 2016 Jun
REPOSITORIES: biostudies-literature
Publications
Immunotherapy for uveal melanoma.
Kim Dae Won DW Anderson Jaime J Patel Sapna P SP
Melanoma management 20160519 2
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 me ...[more]
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Project description:Importance:Uveal 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. Objective:To determine whether there may be a rationale for PRAME-directed T-cell therapy for metastatic UM. Design, Setting, and Participants:An 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 Measures:Interferon ? production for antigen-specific reactivity and detection of PRAME and HLA class I expression in primary and metastatic UM. Results:Of 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 Relevance:PRAME 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.
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