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Detection and Functional Analysis of CD8⁺ T Cells Specific for PRAME: a Target for T-Cell Therapy

Authors' Affiliations: Departments of ¹ Clinical Oncology, ² Immunohematology and Blood Transfusion, and ³ Hematology, Leiden University Medical Center, Leiden, the Netherlands

Requests for reprints: Marieke Griffioen, Department of Hematology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, the Netherlands. Phone: 31-71-5262640; Fax: 31-71-5266755; E-mail: M.Griffioen{at}lumc.nl.

Purpose: Preferentially expressed antigen on melanomas (PRAME) is an interesting antigen for T-cell therapy because it is frequently expressed in melanomas (95%) and other tumor types. Moreover, due to its role in oncogenic transformation, PRAME-negative tumor cells are not expected to easily arise and escape from T-cell immunity. The purpose of this study is to investigate the usefulness of PRAME as target for anticancer T-cell therapies.

Experimental Design: HLA-A*0201-subtyped healthy individuals and advanced melanoma patients were screened for CD8⁺ T cells directed against previously identified HLA-A*0201-binding PRAME peptides by IFN- enzyme-linked immunosorbent spot assays and tetramer staining. PRAME-specific T-cell clones were isolated and tested for recognition of melanoma and acute lymphoid leukemia (ALL) cell lines. PRAME mRNA expression was determined by quantitative real-time reverse transcription-PCR.

Results: In 30% to 40% of healthy individuals and patients, PRA^100-108-specific CD8⁺ T cells were detected both after in vitro stimulation and directly ex vivo after isolation by magnetic microbeads. Although CD45RA^– memory PRA^100-108-specific T cells were found in some individuals, the majority of PRA^100-108-tetramer⁺ T cells expressed CD45RA, suggesting a naive phenotype. PRA^100-108-tetramer⁺ T-cell clones were shown to recognize and lyse HLA-A*0201⁺ and PRAME⁺ melanoma but not ALL cell lines. Quantitative real-time reverse transcription-PCR showed significantly lower PRAME mRNA levels in ALL than in melanoma cell lines, suggesting that PRAME expression in ALL is below the recognition threshold of our PRA^100-108-tetramer⁺ T cells.

Conclusion: These data support the usefulness of PRAME and in particular the PRA^100-108 epitope as target for T-cell therapy of PRAME-overexpressing cancers.

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