PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer

Frontiers in Immunology

Immunology

Peter A. van Veelen¹  Arnoud H. de Ru¹  Tassilo L. A. Wachsmann²  J. H. Frederik Falkenburg²  Dirk M. van der Steen²  Renate S. Hagedoorn²  Sterre L. Siekman²  Anne K. Wouters²  Miranda H. Meeuwsen²  Rosa A. van Amerongen²  Dennis F. G. Remst²  Marian van de Meent²  Mirjam H. M. Heemskerk²  Sander Tuit²  Els M. E. Verdegaal³ 

[1] Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands;Department of Hematology, Leiden University Medical Center, Leiden, Netherlands;Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, Netherlands;

关键词: ovarian cancer;    PRAME;    CTCFL;    CLDN6;    TCR gene transfer;    T-cell therapy;    immunotherapy;    allogeneic HLA;   

DOI  :  10.3389/fimmu.2023.1121973

 received in 2022-12-12, accepted in 2023-02-06,  发布年份 2023

来源: Frontiers

【 摘 要 】

Recurrent disease emerges in the majority of patients with ovarian cancer (OVCA). Adoptive T-cell therapies with T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) are considered promising solutions for less-immunogenic ‘cold’ ovarian tumors. In order to treat a broader patient population, more TCRs targeting peptides derived from different TAAs binding in various HLA class I molecules are essential. By performing a differential gene expression analysis using mRNA-seq datasets, PRAME, CTCFL and CLDN6 were selected as strictly tumor-specific TAAs, with high expression in ovarian cancer and at least 20-fold lower expression in all healthy tissues of risk. In primary OVCA patient samples and cell lines we confirmed expression and identified naturally expressed TAA-derived peptides in the HLA class I ligandome. Subsequently, high-avidity T-cell clones recognizing these peptides were isolated from the allo-HLA T-cell repertoire of healthy individuals. Three PRAME TCRs and one CTCFL TCR of the most promising T-cell clones were sequenced, and transferred to CD8+ T cells. The PRAME TCR-T cells demonstrated potent and specific antitumor reactivity in vitro and in vivo. The CTCFL TCR-T cells efficiently recognized primary patient-derived OVCA cells, and OVCA cell lines treated with demethylating agent 5-aza-2′-deoxycytidine (DAC). The identified PRAME and CTCFL TCRs are promising candidates for the treatment of patients with ovarian cancer, and are an essential addition to the currently used HLA-A*02:01 restricted PRAME TCRs. Our selection of differentially expressed genes, naturally expressed TAA peptides and potent TCRs can improve and broaden the use of T-cell therapies for patients with ovarian cancer or other PRAME or CTCFL expressing cancers.

【 授权许可】

Unknown   
Copyright © 2023 van Amerongen, Tuit, Wouters, van de Meent, Siekman, Meeuwsen, Wachsmann, Remst, Hagedoorn, van der Steen, de Ru, Verdegaal, van Veelen, Falkenburg and Heemskerk