Barish Michael E, Aftabizadeh Maryam, Hibbard Jonathan, Blanchard M Suzette, Ostberg Julie R, Wagner Jamie R, Manchanda Mishika, Paul Jinny, Stiller Tracy, Aguilar Brenda, Starr Renate, Arvanitis Leonidas, Ressler Julie A, Kilpatrick Julie, Kong Yuthana, Wang Dongrui, Forman Stephen J, D'Apuzzo Massimo, Brown Christine E, Badie Behnam
Department of Stem Cell Biology & Regenerative Medicine, City of Hope Beckman Research Institute and Medical Center, Duarte, CA 91010, USA.
Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center, Duarte, CA 91010, USA.
Cell Rep Med. 2025 Aug 19;6(8):102302. doi: 10.1016/j.xcrm.2025.102302. Epub 2025 Aug 15.
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.
治疗胶质母细胞瘤（GBM）的一个挑战在于患者之间以及肿瘤内部的表型异质性。氯毒素（CLTX）是一种来自蝎毒的肽，它通过一种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。我们之前开发了嵌合抗原受体（CAR）T细胞，将CLTX作为GBM识别结构域。在此，我们报告了一项1期试验的中期临床经验，该试验评估了CLTX-CAR T细胞向4例表达MMP-2的复发性GBM患者进行腔内/瘤内（ICT）递送的情况（NCT04214392），主要目的是评估其可行性和安全性。该疗法耐受性良好，没有剂量限制性毒性。四名参与者中有三名（75%）表现出疾病稳定的最佳反应。在肿瘤腔液中检测到了CLTX-CAR T细胞，血液中的水平较低。人抗CAR抗体检测未检测到针对CLTX-CAR的体液免疫原性。这些观察结果支持对CLTX-CAR疗法进行进一步的临床评估。
