Scholarlink

<p>Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, proliferative capacity and effector function of tumor-specific TIL. Here, we develop a platform for the efficient identification of tumor-specific TCR genes from diagnostic tumor biopsies, including core-needle biopsies frozen in a non-viable format, to enable engineered T cell therapy. Using a genetic screening approach that detects antigen-reactive TCRs with high sensitivity and specificity based on T cell activation, we show that high complexity TCR libraries can be efficiently screened against multiplexed antigen libraries to identify both HLA class I and II restricted TCRs. Through the identification of neoantigen-specific TCRs directly from melanoma as well as low tumor mutational burden microsatellite-stable colorectal carcinoma samples, we demonstrate the pan-cancer potential of this platform.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月14日

查看全文
  • Thomas Kuilman,
  • Deborah S. Schrikkema,
  • Jules Gadiot,
  • Raquel Gomez-Eerland,
  • Laura Bies,
  • Julia Walker,
  • Robbert M. Spaapen,
  • Hanna Kok,
  • Demi Houg,
  • Milena Viyacheva,
  • Yvonne B. Claassen,
  • Manuel Saornil,
  • Oscar Krijgsman,
  • Bas Stringer,
  • Huiwen Ding,
  • Anou Geleijnse,
  • Anne C. Meinema,
  • Bianca Weissbrich,
  • Melissa Lancee,
  • Carmen G. Engele,
  • Marianna Sabatino,
  • Pei-Ling Chen,
  • Kenneth Y. Tsai,
  • James J. Mulé,
  • Vernon K. Sondak,
  • Jitske van den Bulk,
  • Noel F. de Miranda,
  • Inge Jedema,
  • John G. Haanen,
  • Jeroen W. J. van Heijst,
  • Ton N. Schumacher,
  • Carsten Linnemann,
  • Gavin M. Bendle

摘要

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, proliferative capacity and effector function of tumor-specific TIL. Here, we develop a platform for the efficient identification of tumor-specific TCR genes from diagnostic tumor biopsies, including core-needle biopsies frozen in a non-viable format, to enable engineered T cell therapy. Using a genetic screening approach that detects antigen-reactive TCRs with high sensitivity and specificity based on T cell activation, we show that high complexity TCR libraries can be efficiently screened against multiplexed antigen libraries to identify both HLA class I and II restricted TCRs. Through the identification of neoantigen-specific TCRs directly from melanoma as well as low tumor mutational burden microsatellite-stable colorectal carcinoma samples, we demonstrate the pan-cancer potential of this platform.