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

• DOI: 10.1016/j.omto.2023.07.007
• Publication Date: 2023-07-28T01:22:32Z
• Authors: Baijin Xia; Keming Lin; Xuemei Wang; FeiLi Chen; Mo Zhou; Yuzhuang Li; Yingtong Lin; Yidan Qiao; Rong Li; Wanying Zhang; Xin He; Fan Zou; Linghua Li; Lijuan Lu; Cancan Chen; WenYu Li; Hui Zhang; Bingfeng Liu
• Keywords: CD30; Neoplasms. Tumors. Oncology. Including cancer and carcinogens; Original Article; bispecific CAR-T cells; nanobodies; RC254-282; 3. Good health; CD5; T cell lymphoma

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 Nb-based bispecific CAR-T cells may improve their safety and efficacy in future clinical applications.