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

M Griffioen, JH Kessler, M Borghi, RA van Soest… - Clinical Cancer …, 2006 - AACR
M Griffioen, JH Kessler, M Borghi, RA van Soest, CE van der Minne, J Nouta…
Clinical Cancer Research, 2006AACR
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 …
Abstract
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-γ 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, PRA100-108-specific CD8+ T cells were detected both after in vitro stimulation and directly ex vivo after isolation by magnetic microbeads. Although CD45RA memory PRA100-108-specific T cells were found in some individuals, the majority of PRA100-108-tetramer+ T cells expressed CD45RA, suggesting a naive phenotype. PRA100-108-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 PRA100-108-tetramer+ T cells.
Conclusion: These data support the usefulness of PRAME and in particular the PRA100-108 epitope as target for T-cell therapy of PRAME-overexpressing cancers.
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