Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Lorry Lokey Building, Suite G3141, MC: 5456, 265 Campus Drive, Stanford, CA 94305, USA.
Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Cancer Cell. 2022 Jan 10;40(1):53-69.e9. doi: 10.1016/j.ccell.2021.12.005. Epub 2021 Dec 30.
Pediatric cancers often mimic fetal tissues and express proteins normally silenced postnatally that could serve as immune targets. We developed T cells expressing chimeric antigen receptors (CARs) targeting glypican-2 (GPC2), a fetal antigen expressed on neuroblastoma (NB) and several other solid tumors. CARs engineered using standard designs control NBs with transgenic GPC2 overexpression, but not those expressing clinically relevant GPC2 site density (∼5,000 molecules/cell, range 1-6 × 10). Iterative engineering of transmembrane (TM) and co-stimulatory domains plus overexpression of c-Jun lowered the GPC2-CAR antigen density threshold, enabling potent and durable eradication of NBs expressing clinically relevant GPC2 antigen density, without toxicity. These studies highlight the critical interplay between CAR design and antigen density threshold, demonstrate potent efficacy and safety of a lead GPC2-CAR candidate suitable for clinical testing, and credential oncofetal antigens as a promising class of targets for CAR T cell therapy of solid tumors.
儿科癌症常模仿胎儿组织，并表达出生后通常沉默的蛋白质，这些蛋白质可作为免疫靶点。我们开发了表达嵌合抗原受体 (CAR) 的 T 细胞，这些受体靶向磷脂酰聚糖-2 (GPC2)，GPC2 是神经母细胞瘤 (NB) 和其他几种实体瘤上表达的胎儿抗原。使用标准设计工程改造的 CAR 可控制过表达转基因 GPC2 的 NB，但不能控制表达临床相关 GPC2 位点密度 (∼5000 个分子/细胞，范围为 1-6×10) 的 NB。跨膜 (TM) 和共刺激结构域的反复工程设计以及 c-Jun 的过表达降低了 GPC2-CAR 抗原密度阈值，从而能够有效且持久地消除表达临床相关 GPC2 抗原密度的 NB，而没有毒性。这些研究强调了 CAR 设计和抗原密度阈值之间的关键相互作用，证明了一种有希望的临床前 GPC2-CAR 候选物具有强大的疗效和安全性，适合临床测试，并证明了肿瘤胎抗原作为 CAR T 细胞治疗实体瘤的一类有前途的靶点。
