肿瘤细胞治疗研究
英文原题：Trial in progress: phase I study of non-viral gene-modified CAR-T cell therapy for malignant solid tumors expressing EPHB4 receptor (CARTiEr).
Trial in progress: phase I study of non-viral gene-modified CAR-T cell therapy for malignant solid tumors expressing EPHB4 receptor (CARTiEr).
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AP8901 的优势在于其有望预防 T 细胞耗竭并维持抗肿瘤作用。
Ephrin B 型受体 4（EPHB4）在多种肿瘤细胞表面过表达，包括恶性骨和软组织肿瘤细胞。AP8901 CAR-T 通过改造 EPHB4 天然配体 ephrin B2，可特异识别并杀伤表达 EPHB4 受体的恶性肿瘤细胞。AP8901 通过 piggyBac 转座子和基因修饰饲养细胞方法进行开发，可使 T 细胞稳定表达 CAR 蛋白并防止 T 细胞耗竭。AP8901 在横纹肌肉瘤细胞移植小鼠中显示治疗效果且耐受性良好。研究者计划开展 I 期研究，评估 AP8901 治疗转移性实体瘤的安全性和疗效。
这是一项单中心、单臂、剂量递增 I 期研究，评估单次静脉给予 AP8901 后的安全性、耐受性、药代动力学/药效学及初步抗肿瘤活性。患者为 Ewing 肉瘤或表达 EPHB4 受体的实体瘤患者。主要入选条件包括：组织学确诊 Ewing 肉瘤或实体瘤，已确认转移或复发且无标准转移/复发治疗，或对标准治疗耐药/不耐受；按 RECIST 1.1 有可测量或可评估疾病；近期活检或手术标本预筛选免疫组化显示至少 1% 肿瘤细胞 EPHB4 阳性；ECOG 体能状态 0 或 1；预计入组后生存至少 3 个月。研究在日本国立癌症中心东医院开展。讨论：AP8901 的优势在于有望防止 T 细胞耗竭并维持抗肿瘤作用。该 I 期研究将为这种新型 CAR-T 用于包括 Ewing 肉瘤在内的实体瘤提供新的临床证据。
Ephrin type-B receptor 4 (EPHB4) is overexpressed on the surface of various tumor cells, including cells from malignant bone and soft-tissue tumors. AP8901 CAR-T cell therapy can specifically recognize and kill EPHB4 receptor-expressing malignant tumor cells by modifying the natural EPHB4 receptor ligand, ephrin B2. AP8901 is being developed via genetic manipulation involving the "piggyBac transposon" and "genetically modified feeder cell" methods, which enables the stable expression of CAR proteins in T cells and prevents T cell exhaustion. AP8901 has demonstrated therapeutic efficacy and tolerability in mice transplanted with rhabdomyosarcoma cells. We planned a phase I study to evaluate the safety and efficacy of AP8901 for metastatic solid tumors.
This is a single-center, single-arm, dose-escalation, phase I study to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary anti-tumor activity of a single intravenous dose of AP8901 in patients with Ewing sarcoma or solid tumors expressing the EPHB4 receptor. Key inclusion criteria include the following: subjects with histologically diagnosed Ewing sarcoma or solid tumor with confirmed metastasis or recurrence/no standard treatment for metastasis or recurrence, or refractory or intolerant to standard treatment; measurable or evaluable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; recent biopsy or surgical resection specimens with prescreening immunohistochemistry positive for EPHB4 in 1% of tumor cells; ECOG performance status 0 or 1; and subjects expected to survive 3 months from the date of enrollment. This study is being conducted at the National Cancer Center Hospital East, Japan. DISCUSSION: The advantage of AP8901 is that it is expected to prevent T cell exhaustion and maintain its anti-tumor effect. This phase 1 study of AP8901 will provide new evidence for the application of this novel CAR-T cell therapy in patients with solid tumors, including Ewing sarcoma.
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