Pre-TCR-targeted immunotherapy for T cell acute lymphoblastic leukemia
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.
Authors
- Ignacio Isola
- Manuel Ramı́rez (ORCID: https://orcid.org/0000-0003-0332-6973)
- Patricia Fuentes (ORCID: https://orcid.org/0000-0003-4597-1022)
- Claudia Cifuentes (ORCID: https://orcid.org/0000-0002-3701-7901)
- Carmela Cela (ORCID: https://orcid.org/0000-0002-2639-658X)
- Mireia Camós (ORCID: https://orcid.org/0000-0003-3658-7942)
- Juan Alcaín (ORCID: https://orcid.org/0000-0003-3282-3231)
- Marina García-Peydró (ORCID: https://orcid.org/0000-0002-8791-132X)
- Marı́a L. Toribio (ORCID: https://orcid.org/0000-0002-8637-0373)
- Montserrat Torrebadell (ORCID: https://orcid.org/0000-0002-0027-3215)
- Balbino Alarcón (ORCID: https://orcid.org/0000-0001-7820-1070)
- Marta Mosquera
Institutions
- Hospital Sant Joan de Déu Barcelona (ES)
- Instituto de Salud Carlos III (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Hospital Infantil Universitario Niño Jesús (ES)
- Centro de Biología Molecular Severo Ochoa (ES)
- Instituto de Investigación de Enfermedades Raras (ES)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- Nature Immunology
- Published
- 2025-09-01
- DOI
- https://doi.org/10.1038/s41590-025-02265-w
- Citations
- 3
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 5.64
Funders
- Brigham and Women's Hospital
- Fundación Ramón Areces
- Sunnybrook Research Institute
- Comunidad de Madrid
- Ministerio de Ciencia, Innovación y Universidades
- Centro de Biología Molecular Severo Ochoa
- Fundación Inocente, Inocente
- European Commission
- Universiteit van Amsterdam
- University of Toronto
- European Regional Development Fund
- Agencia Estatal de Investigación
- Centro Nacional de Biotecnología