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
{"title":"纳米体衍生的双特异性CAR-T细胞疗法增强了T细胞淋巴瘤治疗的抗肿瘤疗效。","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","doi":"10.1016/j.omto.2023.07.007","DOIUrl":null,"url":null,"abstract":"<p><p>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 <i>in vitro</i> and <i>in vivo</i>. 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.</p>","PeriodicalId":18869,"journal":{"name":"Molecular Therapy Oncolytics","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/53/6d/main.PMC10427987.pdf","citationCount":"1","resultStr":"{\"title\":\"Nanobody-derived bispecific CAR-T cell therapy enhances the anti-tumor efficacy of T cell lymphoma treatment.\",\"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\",\"doi\":\"10.1016/j.omto.2023.07.007\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>T cell lymphoma (TCL) is a highly heterogeneous group of diseases with a poor prognosis and low 5-year overall survival rate. 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Nanobody-derived bispecific CAR-T cell therapy enhances the anti-tumor efficacy of T cell lymphoma treatment.
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.
期刊介绍:
Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.