Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirus

Liao, Qibin1,2,3; Liu, Zhuoqun1,2; Zhu, Cuisong1,2; He, Huan1,2; Feng, Meiqi1,2; Jiang, Lang1,2; Ding, Xiangqing1,2; Sun, Rongxun4; Zhang, Xiaoyan1,2; Xu, Jianqing1,2

2023-05-01

10.1016/j.jare.2022.08.008

JOURNAL OF ADVANCED RESEARCH   影响因子和分区

2090-1232

2090-1224

Introduction: The on-target off-tumor toxicity of chimeric antigen receptor-engineered T cells (CAR-T) might lead to fatal side effects in cancer patients, which remains as a major obstacle to the clinical appli-cation of CAR-T immunotherapy. The off-tumor on-target normal tissue toxicity of CAR-T cells needs to be evaluated in preclinical studies using rational animal models.Objectives: We aim to develop a rational animal model for assessing the off-tumor on-target normal tis-sue toxicity of various CAR-T cell designs quickly.Methods: We used a recombinant adenovirus type 5 carrying human HER2/ERBB2 (Ad5-HER2) or CD47 gene (Ad5-CD47) to rapidly generate a mouse model with tunable human antigen expression on normal liver tissue to determine immunotoxicity of traditional CAR-T and hypoxia-response CAR-T cells in vivo.Results: The obvious liver damage and lymphocyte infiltration were not observed in mice with human antigen-high livers 8 days post-infection. Interestingly, the lethal liver damage, systemic cytokine release and CAR-T cells infiltration in liver were only observed in mice that received traditional CAR-T cells, but not in hypoxia-response CAR-T cells.Conclusion: Adenovirus-based expression of target antigen in normal mouse tissue may be a useful method for assessing on-target CAR-T cell toxicity in normal tissues, especially various CAR-T cell designs that have the potency of conditional regulation in tumor microenvironment (TME).(c) 2023 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

CAR-T On-target off-tumor toxicity Normal tissue Animal model Adenovirus

SCI

英语

其他

Clinical Research Plan of SHDC["SHDC2020CR3002A","SHDC12018112"] ; National Key Research and Development Program of China[2016YFC1303402] ; National Megaproject on Key Infectious Diseases["2017ZX10202102","2017ZX10304402-002-007","2017ZX10304402-001-006"] ; Shenzhen Third People's Hospital["G2022091","G2022033"]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000991215700001

ELSEVIER

Web of Science

1.Fudan Univ, Zhongshan Hosp, Inst Biomed Sci, Shanghai, Peoples R China
2.Fudan Univ, Shanghai Publ Hlth Clin Ctr, Shanghai, Peoples R China
3.Southern Univ Sci & Technol, Shenzhen Peoples Hosp 3, Hosp 2, Biotherapeut Ctr,Dept Oncol, Shenzhen, Peoples R China
4.Fudan Univ, Jinshan Hosp, Dept Gen Surg, Shanghai, Peoples R China

Liao, Qibin,Liu, Zhuoqun,Zhu, Cuisong,et al. Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirus[J]. JOURNAL OF ADVANCED RESEARCH,2023,47.

Liao, Qibin.,Liu, Zhuoqun.,Zhu, Cuisong.,He, Huan.,Feng, Meiqi.,...&Xu, Jianqing.(2023).Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirus.JOURNAL OF ADVANCED RESEARCH,47.

Liao, Qibin,et al."Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirus".JOURNAL OF ADVANCED RESEARCH 47(2023).