Department of Radiation Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China.
Guangdong Procapzoom Bioscience Inc, Guangzhou, Guangdong, China.
Front Immunol. 2024 Mar 19;15:1337489. doi: 10.3389/fimmu.2024.1337489. eCollection 2024.
Chimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid tumors.
In this study, we created CD276-targeted CAR-expressing NK cells from pluripotent stem cells (iPSC CD276-targeted CAR-NK cells) and evaluated their cytotoxicity against esophageal squamous cell carcinoma (ESCC) using patient-specific organoid (PSO) models comprising of both CD276-positive and CD276-negative adjacent epithelium PSO models (normal control PSO, NC PSO) as well as primary culture of ESCC cell models. In addition, and models such as KYSE-150 were also examined. iPSC NK cells and NK-free media were used as the CAR-free and NK-free controls, respectively.
The positive CD276 staining was specifically detected on the ESCC membrane in 51.43% (54/105) of the patients of all stages, and in 51.35% (38/74) of stages III and IV. The iPS CD276-targeted CAR-NK cells, comparing with the iPS NK cells and the NK-free medium, exhibited specific and significant cytotoxic activity against CD276-positive ESCC PSO rather than CD276-negative NC PSO, and exhibited significant cytotoxicity against CD276-expressing cultured ESCC cells, as well as against CD276-expressing KYSE-150 and in BNDG mouse xenograft.
The efficacy of the iPSC CD276-targeted CAR-NK cells demonstrated by their successful treatment of CD276-expressing ESCC in a multitude of pre-clinical models implied that they hold tremendous therapeutic potential for treating patients with CD276-expressing ESCC.
嵌合抗原受体自然杀伤 (CAR-NK) 细胞已被证明在治疗血液恶性肿瘤方面取得成功，并具有在实体瘤中应用的潜力。
在这项研究中，我们从多能干细胞（iPSC CD276 靶向 CAR-NK 细胞）中创建了靶向 CD276 的 CAR 表达 NK 细胞，并使用包含 CD276 阳性和 CD276 阴性相邻上皮的患者特异性类器官 (PSO) 模型评估其对食管鳞状细胞癌 (ESCC) 的细胞毒性，PSO 模型（正常对照 PSO，NC PSO）以及 ESCC 细胞模型的原代培养。此外，还检查了 KYSE-150 等 模型。iPSC NK 细胞和无 NK 培养基分别用作无 CAR 和无 NK 对照。
所有分期的 105 例患者中有 51.43%（54/105）和 III 期和 IV 期的 51.35%（38/74）患者的 ESCC 膜上特异性检测到阳性 CD276 染色。与 iPS NK 细胞和无 NK 培养基相比，iPS CD276 靶向 CAR-NK 细胞对 CD276 阳性 ESCC PSO 表现出特异性和显著的细胞毒性，而对 CD276 阴性 NC PSO 没有表现出这种作用，并且对表达 CD276 的培养 ESCC 细胞以及表达 CD276 的 KYSE-150 细胞和 BNDG 小鼠异种移植瘤具有显著的细胞毒性。
iPSC CD276 靶向 CAR-NK 细胞在多种临床前模型中成功治疗 CD276 表达的 ESCC 所证明的疗效表明，它们具有巨大的治疗 CD276 表达的 ESCC 患者的治疗潜力。
