PMID- 36411612 OWN - NLM STAT- MEDLINE DCOM- 20221123 LR - 20221123 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 156 DP - 2022 Dec TI - Nanobody-based CAR T cells targeting intracellular tumor antigens. PG - 113919 LID - S0753-3322(22)01308-7 [pii] LID - 10.1016/j.biopha.2022.113919 [doi] AB - 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 mouse tumor models. This study offers a possible strategy for targeting intracellular antigens and widening the application of CAR T-cell therapy. CI - Copyright (c) 2022. Published by Elsevier Masson SAS. FAU - Li, Haixia AU - Li H AD - 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. FAU - Zhong, Dani AU - Zhong D AD - 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. FAU - Luo, Huiguan AU - Luo H AD - 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. FAU - Shi, Wei AU - Shi W AD - 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. FAU - Xie, Shenxia AU - Xie S AD - 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. FAU - Qiang, Hangbiao AU - Qiang H AD - 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. FAU - Zhu, Lichen AU - Zhu L AD - 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. FAU - Gao, Li AU - Gao L AD - 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. FAU - Liu, Jun AU - Liu J AD - 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. FAU - Sun, Shuyang AU - Sun S AD - 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. FAU - Ding, Ziqiang AU - Ding Z AD - 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. FAU - Yang, Xiaomei AU - Yang X AD - 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. FAU - Lu, Xiaoling AU - Lu X AD - 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. LA - eng PT - Journal Article DEP - 20221027 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Antigens, Neoplasm) RN - 0 (HLA-A2 Antigen) RN - 0 (Single-Domain Antibodies) RN - 0 (GPC3 protein, human) RN - 0 (Glypicans) SB - IM MH - Humans MH - Animals MH - Mice MH - Antigens, Neoplasm MH - HLA-A2 Antigen MH - *Single-Domain Antibodies MH - *Wilms Tumor MH - *Kidney Neoplasms MH - T-Lymphocytes MH - Glypicans OTO - NOTNLM OT - CAR T-cell therapy OT - Intracellular tumor antigen OT - Nanobody OT - TCR-like antibody COIS- Conflict of interest statement The authors declare that there are no conflicts of interest. EDAT- 2022/11/23 06:00 MHDA- 2022/11/24 06:00 CRDT- 2022/11/22 01:13 PHST- 2022/08/18 00:00 [received] PHST- 2022/10/18 00:00 [revised] PHST- 2022/10/24 00:00 [accepted] PHST- 2022/11/22 01:13 [entrez] PHST- 2022/11/23 06:00 [pubmed] PHST- 2022/11/24 06:00 [medline] AID - S0753-3322(22)01308-7 [pii] AID - 10.1016/j.biopha.2022.113919 [doi] PST - ppublish SO - Biomed Pharmacother. 2022 Dec;156:113919. doi: 10.1016/j.biopha.2022.113919. Epub 2022 Oct 27.