Chlorotoxin-directed CAR T cell therapy for recurrent glioblastoma: Interim clinical experience demonstrating feasibility and safety.

IF 10.6 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-08-19 Epub Date: 2025-08-15 DOI:10.1016/j.xcrm.2025.102302

Michael E Barish, Maryam Aftabizadeh, Jonathan Hibbard, M Suzette Blanchard, Julie R Ostberg, Jamie R Wagner, Mishika Manchanda, Jinny Paul, Tracy Stiller, Brenda Aguilar, Renate Starr, Leonidas Arvanitis, Julie A Ressler, Julie Kilpatrick, Yuthana Kong, Dongrui Wang, Stephen J Forman, Massimo D'Apuzzo, Christine E Brown, Behnam Badie

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引用次数: 0

Abstract

A challenge in treating glioblastoma (GBM) is its phenotypic heterogeneity between patients and within tumors. Chlorotoxin (CLTX), a peptide from scorpion venom, broadly binds glioma cells through a mechanism involving surface matrix metalloproteinase-2 (MMP-2). We previously developed chimeric antigen receptor (CAR) T cells incorporating CLTX as the GBM recognition domain. Here, we report interim clinical experience of a phase 1 trial evaluating intracavity/intratumoral (ICT) delivery of CLTX-CAR T cells in four patients with MMP-2-expressing recurrent GBM (NCT04214392), with the primary objectives of feasibility and safety. The therapy is well tolerated with no dose-limiting toxicities. Three of the four participants (75%) exhibit a best response of stable disease. CLTX-CAR T cells are detected in the tumor cavity fluid and at lower levels in the blood. Human anti-CAR antibody assays do not detect humoral immunogenicity against the CLTX-CAR. These observations support further clinical evaluation of CLTX-CAR therapy.

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氯毒素靶向CAR - T细胞治疗复发性胶质母细胞瘤：证明可行性和安全性的中期临床经验。

治疗胶质母细胞瘤（GBM）的一个挑战是其患者之间和肿瘤内的表型异质性。氯毒素（CLTX）是一种来自蝎子毒液的肽，通过涉及表面基质金属蛋白酶-2 （MMP-2）的机制广泛结合胶质瘤细胞。我们之前开发了将CLTX作为GBM识别域的嵌合抗原受体（CAR） T细胞。在这里，我们报告了一项1期试验的中期临床经验，该试验评估了4例表达mmp -2的复发性GBM （NCT04214392）患者的腔内/瘤内（ICT）递送CLTX-CAR - T细胞的可行性和安全性。该疗法耐受性良好，无剂量限制性毒性。四名参与者中的三名（75%）表现出稳定疾病的最佳反应。CLTX-CAR - T细胞在肿瘤腔液中检测到，在血液中检测到的水平较低。人抗car抗体检测不能检测针对CLTX-CAR的体液免疫原性。这些观察结果支持CLTX-CAR治疗的进一步临床评估。

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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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.