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<p>Targeted immunotherapy for T cell acute lymphoblastic leukemia (T-ALL), an aggressive tumor of developing T cell progenitors, is an urgent unmet need, especially for relapsed/refractory disease. Selective T-ALL targeting is challenging due to the shared antigen expression between leukemic and normal T cells. Here we identify the pre-T cell receptor (pre-TCR), a surface receptor essential for T cell development, as a biomarker of leukemia-initiating cells (LICs) in human T-ALL. Loss-of-function genetic approaches demonstrate that pre-TCR signaling is necessary for LIC activity and tumor progression in pre-TCR<sup>+</sup> T-ALL patient xenografts in mice. Furthermore, we demonstrate the specific therapeutic targeting of the pre-TCR with a monoclonal antibody against the invariant pTα subunit of the human pre-TCR, and validate an anti-pTα antibody–drug conjugate in vivo treatment as a potent immunotherapy for inhibiting LIC activity and tumor progression of T-ALL in mice. These findings reveal the suitability of pre-TCR targeting as a promising therapy for the treatment of individuals with relapsed/refractory T-ALL expressing the pre-TCR.</p>

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Pre-TCR-targeted immunotherapy for T cell acute lymphoblastic leukemia

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月1日

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  • Patricia Fuentes,
  • Marina García-Peydró,
  • Juan Alcain,
  • Marta Mosquera,
  • Carmela Cela,
  • Claudia Cifuentes,
  • Montserrat Torrebadell,
  • Ignacio Isola,
  • Mireia Camós,
  • Manuel Ramírez,
  • Balbino Alarcón,
  • María L. Toribio

摘要

Targeted immunotherapy for T cell acute lymphoblastic leukemia (T-ALL), an aggressive tumor of developing T cell progenitors, is an urgent unmet need, especially for relapsed/refractory disease. Selective T-ALL targeting is challenging due to the shared antigen expression between leukemic and normal T cells. Here we identify the pre-T cell receptor (pre-TCR), a surface receptor essential for T cell development, as a biomarker of leukemia-initiating cells (LICs) in human T-ALL. Loss-of-function genetic approaches demonstrate that pre-TCR signaling is necessary for LIC activity and tumor progression in pre-TCR+ T-ALL patient xenografts in mice. Furthermore, we demonstrate the specific therapeutic targeting of the pre-TCR with a monoclonal antibody against the invariant pTα subunit of the human pre-TCR, and validate an anti-pTα antibody–drug conjugate in vivo treatment as a potent immunotherapy for inhibiting LIC activity and tumor progression of T-ALL in mice. These findings reveal the suitability of pre-TCR targeting as a promising therapy for the treatment of individuals with relapsed/refractory T-ALL expressing the pre-TCR.