马德里自治大学María L. Toribio小组的最新研究提出了T细胞急性淋巴细胞白血病的TCR前靶向免疫治疗。该项研究成果发表在2025年9月1日出版的《自然—免疫学》上。

在这里，该团队确定了T细胞前受体（pre-TCR），一种T细胞发育所必需的表面受体，作为人类T-ALL中白血病起始细胞（LICs）的生物标志物。功能丧失遗传学方法表明，TCR前信号传导对于小鼠pre-TCR+ T-ALL异种移植患者的LIC活性和肿瘤进展是必要的。

此外，该团队证明了针对人TCR前的不变pTα亚基的单克隆抗体对TCR前的特异性治疗靶向性，并验证了抗pTα抗体-药物偶联物在体内治疗作为抑制小鼠T-ALL的LIC活性和肿瘤进展的有效免疫疗法。这些研究结果表明，靶向治疗TCR前基因表达的复发/难治性T-ALL是一种有希望的治疗方法。

据悉，T细胞急性淋巴细胞白血病（T-ALL）是一种发展中的T细胞祖细胞的侵袭性肿瘤，靶向免疫治疗是一个迫切的未满足的需求，特别是对于复发/难治性疾病。选择性T-ALL靶向是具有挑战性的，因为白血病和正常T细胞之间有共同的抗原表达。

附：英文原文

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

Author: Fuentes, Patricia, Garca-Peydr, Marina, Alcain, Juan, Mosquera, Marta, Cela, Carmela, Cifuentes, Claudia, Torrebadell, Montserrat, Isola, Ignacio, Cams, Mireia, Ramrez, Manuel, Alarcn, Balbino, Toribio, Mara L.

Issue&Volume: 2025-09-01

Abstract: 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.

DOI: 10.1038/s41590-025-02265-w

Source: https://www.nature.com/articles/s41590-025-02265-w