嵌合抗原受体-T细胞治疗儿童肿瘤的临床研究进展

Progress in clinical studies of chimeric antigen receptor engineered T cells for treatment of childhood cancer

摘要:

儿童肿瘤患者的5年生存率已达80%以上，但仍有部分复发难治性肿瘤通过传统治疗手段难以取得理想疗效。嵌合抗原受体（CAR）-T细胞技术的发展为治愈这些肿瘤带来了希望。CAR-T细胞通过非MHC限制性的方式识别肿瘤相关抗原，抗肿瘤能力显著增强，目前已发展到第四代。靶向CD19的CAR-T细胞治疗复发难治性急性淋巴细胞白血病缓解率高达90%，且可以通过桥接造血干细胞移植、供者CAR-T细胞输注等手段辅助白血病的治疗。实体瘤方面，靶向GD2的CAR-T细胞治疗神经母细胞瘤具有良好的反应性，但对其他实体瘤效果欠佳。CAR-T细胞治疗可能出现细胞因子释放综合征、脱靶效应、肿瘤溶解综合征、插入突变等毒副反应。靶向CD19的CAR-T细胞治疗虽有很高的缓解率，但复发率较高，包括CD19⁺和CD19^-复发，其机制尚需进一步研究。

Abstract:

Nowadays, the 5-year survival rate of childhood cancer patients can be more than 80%, but some patients with relapse and refractory cancers have shown no good response to traditional strategies. Chimeric antigen receptor engineered T (CAR-T) cell therapy is promising for these patients. CAR-T cells recognize the tumor-associated antigens in a non-major histocompatibility complex-restricted manner, so their anti-tumor ability is enhanced. There are four generations of CAR-T cells now. The complete remission rate of pediatric patients with relapse and refractory acute lymphoblastic leukemia can be as high as 90% when treated with CD19-targeting CAR-T cells. Furthermore, CAR-T cell therapy can also be used to bridge to transplantation and donor CAR-T cell infusion can be a strategy to prevent relapse after hematopoietic stem cell transplantation. As to solid tumors, only patients with neuroblastoma present good response to the GD2-targeting CAR-T cell therapy. The toxic or side effects of CAR-T cell therapy include cytokine release syndrome, off-tumor effect, tumor lysis syndrome, and insertion mutation. Although the CD19-targeting CAR-T cell therapy for childhood cancer can result in a high remission rate, the relapse rate is high, including CD19⁺ and CD19^- relapse. The mechanisms for relapse merit further investigation.