Nanobody-based CAR T cells targeting intracellular tumor antigens.
Haixia Li, Dani Zhong, Huiguan Luo, Wei Shi, Shenxia Xie, Hangbiao Qiang, Lichen Zhu, Li Gao, Jun Liu, Shuyang Sun, Ziqiang Ding, Xiaomei Yang, Xiaoling Lu
Author Information
Haixia Li: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; School of Basic Medical Sciences, Guangxi Medical University, Nanning, China.
Dani Zhong: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; National Center for International Research of Bio-targeting Theranostics, Guangxi Key Laboratory of Bio-targeting Theranostics, Collaborative Innovation Center for Targeting tumor Diagnosis and Therapy, Guangxi Talent Highland of Bio-targeting Theranostics, Guangxi Medical University, Nanning, China; Oncology Medical College, Guangxi Medical University, Nanning, China.
Huiguan Luo: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; The Second Clinical Medical College, Guangxi Medical University, Nanning, China.
Wei Shi: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Laboratory Animal Center, Guangxi Medical University, Nanning, China.
Shenxia Xie: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Pharmaceutical College, Guangxi Medical University, Nanning, China.
Hangbiao Qiang: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; School of Basic Medical Sciences, Guangxi Medical University, Nanning, China.
Lichen Zhu: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China.
Li Gao: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; School of Basic Medical Sciences, Guangxi Medical University, Nanning, China.
Jun Liu: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China.
Shuyang Sun: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China.
Ziqiang Ding: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; School of Basic Medical Sciences, Guangxi Medical University, Nanning, China.
Xiaomei Yang: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; School of Basic Medical Sciences, Guangxi Medical University, Nanning, China. Electronic address: yxm@gxmu.edu.cn.
Xiaoling Lu: Guangxi Key Laboratory of Nanobody Research, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China; Guangxi Nanobody Engineering Research Center, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China. Electronic address: luxiaoling@gxmu.edu.
Chimeric antigen receptor (CAR) T-cell immunotherapy has become one of the research hotspots in the treatment of malignant tumors nowadays. However, the available tumor surface antigens are limited in number. Most tumor-associated antigens are intracellular molecules that can't be targeted by conventional CAR T cells. As the major histocompatibility complex (MHC)/peptide complex is a presentation form of intracellular proteins on the surface of tumor cells, here, we chose the Glypican-3 (GPC3) oncoprotein and Wilms tumor 1 (WT1) oncoprotein as examples to explore whether nanobody (Nb)-based T cell receptor (TCR)-like CAR T cells could kill tumor cells by targeting the MHC/peptide complexes. Using the immune nanobody phage display library, we developed human leukocyte antigen (HLA)-A2/GPC3- and HLA-A2/WT1-specific nanobodies for the first time and then incorporated these nanobodies in two TCR-like CARs, targeting HLA-A2/GPC3 and HLA-A2/WT1 respectively. These TCR-like Nb CAR-redirected T cells could selectively recognize and lyse MHC/peptide complex-expressing tumor cells in vitro assays and subcutaneous mousetumor models. This study offers a possible strategy for targeting intracellular antigens and widening the application of CAR T-cell therapy.
