Xia Baijin, Lin Keming, Wang Xuemei, Chen FeiLi, Zhou Mo, Li Yuzhuang, Lin Yingtong, Qiao Yidan, Li Rong, Zhang Wanying, He Xin, Zou Fan, Li Linghua, Lu Lijuan, Chen Cancan, Li WenYu, Zhang Hui, Liu Bingfeng
Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Science, Guangzhou 510080, China.
Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Science, Southern Medical University, Guangzhou 510080, China.
Mol Ther Oncolytics. 2023 Jul 28;30:86-102. doi: 10.1016/j.omto.2023.07.007. eCollection 2023 Sep 21.
T cell lymphoma (TCL) is a highly heterogeneous group of diseases with a poor prognosis and low 5-year overall survival rate. The current therapeutic regimens have relatively low efficacy rates. Clinical studies of single-target chimeric antigen receptor T cell (CAR-T cell) therapy in T lymphocytes require large and multiple infusions, increasing the risks and cost of treatment; therefore, optimizing targeted therapy is a way to improve overall prognosis. Despite significant advances in bispecific CAR-T cell therapy to avoid antigen escape in treatment of B cell lymphoma, applying this strategy to TCL requires further investigation. Here, we constructed an alpaca nanobody (Nb) phage library and generated high-affinity and -specificity Nbs targeting CD30 and CD5, respectively. Based on multiple rounds of screening, bispecific NbCD30-CD5-CAR T cells were constructed, and their superior anti-tumor effect against TCL was validated and . Our findings demonstrated that Nb-derived bispecific CAR-T cells significantly improved anti-tumor efficacy in TCL treatment compared with single-target CAR-T cells and bispecific single chain variable fragment (scFv)-derived CAR-T cells. Because Nbs are smaller and less immunogenic, the synergistic effect of Nb-based bispecific CAR-T cells may improve their safety and efficacy in future clinical applications.
T细胞淋巴瘤（TCL）是一组高度异质性的疾病，预后较差，5年总生存率较低。目前的治疗方案疗效相对较低。T淋巴细胞单靶点嵌合抗原受体T细胞（CAR-T细胞）治疗的临床研究需要大量多次输注，增加了治疗风险和成本；因此，优化靶向治疗是改善总体预后的一种方法。尽管双特异性CAR-T细胞疗法在治疗B细胞淋巴瘤以避免抗原逃逸方面取得了重大进展，但将该策略应用于TCL仍需进一步研究。在此，我们构建了一个羊驼纳米抗体（Nb）噬菌体文库，并分别产生了靶向CD30和CD5的高亲和力和特异性Nb。基于多轮筛选，构建了双特异性NbCD30-CD5-CAR T细胞，并验证了其对TCL的优异抗肿瘤作用。我们的研究结果表明，与单靶点CAR-T细胞和双特异性单链可变片段（scFv）衍生的CAR-T细胞相比，Nb衍生的双特异性CAR-T细胞在TCL治疗中显著提高了抗肿瘤疗效。由于Nb更小且免疫原性更低，基于Nb的双特异性CAR-T细胞的协同效应可能会在未来的临床应用中提高其安全性和疗效。
