Nanobody-derived bispecific CAR-T cell therapy enhances the anti-tumor efficacy of T cell lymphoma treatment

作者：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^*

来源：Molecular Therapy-Oncolytics, 2023, 30: 86-102.

DOI：10.1016/j.omto.2023.07.007

• CHIMERIC ANTIGEN RECEPTOR
• ACUTE LYMPHOBLASTIC-LEUKEMIA
• BRENTUXIMAB VEDOTIN
• HODGKIN LYMPHOMA
• OPEN-LABEL
• PHASE-II
• EXPRESSION
• ANTIBODIES
• IMMUNOTHERAPY
• MALIGNANCIES

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 in vitro and in vivo. 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 Nbbased bispecific CAR-T cells may improve their safety and effi- cacy in future clinical applications.

• 单位
  1; 广州医学院; 广东省心血管病研究所; 南方医科大学; 广东省人民医院; 中山大学