K12-ligand-based CAR T cell therapy for CD7-positive T cell malignancies.

Molecular therapy. Oncology Pub Date : 2025-04-29 eCollection Date: 2025-06-18 DOI:10.1016/j.omton.2025.200988
Nienke Visser, Macarena González-Corrales, Jimena Álvarez-Freile, Maurien G Pruis, Lena Rockstein, Harm Jan Lourens, Jan Jacob Schuringa, Tom van Meerten, Gerwin Huls, Edwin Bremer
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Abstract

Chimeric antigen receptor (CAR)-based therapy is of interest for relapsed or refractory (r/r) T cell acute lymphoblastic leukemia (T-ALL) and T cell lymphomas. A prominent target antigen for this is the receptor CD7, which is expressed in ∼95% of T-ALL, ∼50% of peripheral T cell lymphomas, as well as 10% of acute myeloid leukemias. Here, we preclinically evaluated and compared CD7-targeted ligand K12-based CAR-T to an scFvCD7-based CAR-T construct. K12 CAR-T cells produced significantly higher interferon gamma (IFN-γ) after CD7 activation compared to scFv-CD7 CAR-T cells. Similarly, in a JurkatNFAT-luc reporter cell line expressing the respective CAR, CD7-induced luminescence was significantly higher by the K12 CAR than the scFv-CD7 CAR. K12 CAR-T treatment selectively and specifically eliminated a panel of CD7-positive, but not CD7-negative, cell lines and eliminated acute-T-cell-leukemia-patient-derived and acute myeloid leukemia blasts in an effector-to-target ratio-dependent manner. Further, K12 CAR-T cells had prominent anti-leukemic activity in an intravenously (i.v.) injected Jurkat leukemia mouse model, with no detectable disease in three out of five mice treated with K12 CAR-T. Therefore, K12 CAR T cell therapy might be of use for the treatment of r/r patients with CD7-positive T cell leukemia/lymphoma and acute myeloid leukemia (AML).

基于k12配体的CAR - T细胞治疗cd7阳性T细胞恶性肿瘤。
嵌合抗原受体(CAR)为基础的治疗是复发或难治性(r/r) T细胞急性淋巴细胞白血病(T- all)和T细胞淋巴瘤的兴趣。一个重要的靶抗原是受体CD7,它在约95%的T- all、约50%的外周T细胞淋巴瘤和10%的急性髓性白血病中表达。在这里,我们临床前评估并比较了基于cd7靶向配体k12的CAR-T和基于scfvcd7的CAR-T构建。与scFv-CD7 CAR-T细胞相比,K12 CAR-T细胞在CD7活化后显著产生更高的干扰素γ (IFN-γ)。同样,在表达各自CAR的JurkatNFAT-luc报告细胞系中,K12 CAR诱导的cd7发光明显高于scFv-CD7 CAR。K12 CAR-T治疗选择性地和特异性地消除了一组cd7阳性而非cd7阴性的细胞系,并以效应靶比依赖的方式消除了急性t细胞白血病患者来源和急性髓性白血病原细胞。此外,K12 CAR-T细胞在静脉注射Jurkat白血病小鼠模型中具有突出的抗白血病活性,在接受K12 CAR-T治疗的5只小鼠中有3只未检测到疾病。因此,K12 CAR - T细胞疗法可能用于治疗患有cd7阳性T细胞白血病/淋巴瘤和急性髓性白血病(AML)的r/r患者。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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