Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
SJD Pediatric Cancer Center Barcelona, Hospital Sant Joan de Deu, Institut de Recerca Sant Joan de Deu, Barcelona, Spain.
Clin Cancer Res. 2024 Aug 15;30(16):3578-3591. doi: 10.1158/1078-0432.CCR-24-0221.
Retinoblastoma is the most common intraocular malignancy in children. Although new chemotherapeutic approaches have improved ocular salvage rates, novel therapies are required for patients with refractory intraocular and metastatic disease. Chimeric antigen receptor (CAR) T cells targeting glypican-2 (GPC2) are a potential new therapeutic strategy.
GPC2 expression and its regulation by the E2F1 transcription factor were studied in retinoblastoma patient samples and cellular models. In vitro, we performed functional studies comparing GPC2 CAR T cells with different costimulatory domains (4-1BB and CD28). In vivo, the efficacy of local and systemic administration of GPC2 CAR T cells was evaluated in intraocular and leptomeningeal human retinoblastoma xenograft models.
Retinoblastoma tumors, but not healthy retinal tissues, expressed cell surface GPC2, and this tumor-specific expression was driven by E2F1. GPC2-directed CARs with 4-1BB costimulation (GPC2.BBz) were superior to CARs with CD28 stimulatory domains (GPC2.28z), efficiently inducing retinoblastoma cell cytotoxicity and enhancing T-cell proliferation and polyfunctionality. In vivo, GPC2.BBz CARs had enhanced persistence, which led to significant tumor regression compared with either control CD19 or GPC2.28z CARs. In intraocular models, GPC2.BBz CAR T cells efficiently trafficked to tumor-bearing eyes after intravitreal or systemic infusions, significantly prolonging ocular survival. In central nervous system (CNS) retinoblastoma models, intraventricular or systemically administered GPC2.BBz CAR T cells were activated in retinoblastoma-involved CNS tissues, resulting in robust tumor regression with substantially extended overall mouse survival.
GPC2-directed CAR T cells are effective against intraocular and CNS metastatic retinoblastomas.
视网膜母细胞瘤是儿童中最常见的眼内恶性肿瘤。尽管新的化疗方法提高了眼保存率，但对于患有难治性眼内和转移性疾病的患者，仍需要新的治疗方法。靶向磷脂酰聚糖-2（GPC2）的嵌合抗原受体（CAR）T 细胞是一种潜在的新治疗策略。
研究了 GPC2 在视网膜母细胞瘤患者样本和细胞模型中的表达及其受 E2F1 转录因子的调节。在体外，我们进行了功能研究，比较了具有不同共刺激结构域（4-1BB 和 CD28）的 GPC2 CAR T 细胞。在体内，评估了局部和全身给予 GPC2 CAR T 细胞在眼内和软脑膜人视网膜母细胞瘤异种移植模型中的疗效。
视网膜母细胞瘤肿瘤，但不是健康的视网膜组织，表达细胞表面 GPC2，这种肿瘤特异性表达是由 E2F1 驱动的。具有 4-1BB 共刺激（GPC2.BBz）的 GPC2 定向 CAR 比具有 CD28 刺激结构域（GPC2.28z）的 CAR 更有效，可有效诱导视网膜母细胞瘤细胞细胞毒性，并增强 T 细胞增殖和多功能性。在体内，GPC2.BBz CAR 具有增强的持久性，与对照 CD19 或 GPC2.28z CAR 相比，导致显著的肿瘤消退。在眼内模型中，GPC2.BBz CAR T 细胞在玻璃体内或全身输注后有效地转移到肿瘤眼，显著延长了眼存活率。在中枢神经系统（CNS）视网膜母细胞瘤模型中，脑室或系统给予的 GPC2.BBz CAR T 细胞在涉及 CNS 的视网膜母细胞瘤组织中被激活，导致强大的肿瘤消退，并显著延长了整体小鼠存活时间。
GPC2 定向 CAR T 细胞对眼内和 CNS 转移性视网膜母细胞瘤有效。
