Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirus
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 application of CAR-T immunotherapy. The off-tumor on-target normal tissue toxicity of CAR-T ce...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Journal of Advanced Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123222001898 |
| _version_ | 1797837808162832384 |
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| author | Qibin Liao Zhuoqun Liu Cuisong Zhu Huan He Meiqi Feng Lang Jiang Xiangqing Ding Rongxun Sun Xiaoyan Zhang Jianqing Xu |
| author_facet | Qibin Liao Zhuoqun Liu Cuisong Zhu Huan He Meiqi Feng Lang Jiang Xiangqing Ding Rongxun Sun Xiaoyan Zhang Jianqing Xu |
| author_sort | Qibin Liao |
| collection | DOAJ |
| description | 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 application 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 tissue 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). |
| first_indexed | 2024-04-09T15:30:38Z |
| format | Article |
| id | doaj.art-e7f3ea80a48e436eaed7cc7ba82f1d46 |
| institution | Directory Open Access Journal |
| issn | 2090-1232 |
| language | English |
| last_indexed | 2024-04-09T15:30:38Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj.art-e7f3ea80a48e436eaed7cc7ba82f1d462023-04-28T08:55:20ZengElsevierJournal of Advanced Research2090-12322023-05-0147163171Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirusQibin Liao0Zhuoqun Liu1Cuisong Zhu2Huan He3Meiqi Feng4Lang Jiang5Xiangqing Ding6Rongxun Sun7Xiaoyan Zhang8Jianqing Xu9Zhongshan Hospital, Institutes of Biomedical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Department of Oncology and Bio-therapeutic Center, Shenzhen Third People's Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, ChinaZhongshan Hospital, Institutes of Biomedical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, ChinaZhongshan Hospital, Institutes of Biomedical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, ChinaZhongshan Hospital, Institutes of Biomedical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, ChinaZhongshan Hospital, Institutes of Biomedical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, ChinaZhongshan Hospital, Institutes of Biomedical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, ChinaZhongshan Hospital, Institutes of Biomedical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, ChinaDepartment of General Surgery, Jinshan Hospital of Fudan University, Shanghai, China; Corresponding authors.Zhongshan Hospital, Institutes of Biomedical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Corresponding authors.Zhongshan Hospital, Institutes of Biomedical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China; Corresponding authors.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 application 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 tissue 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).http://www.sciencedirect.com/science/article/pii/S2090123222001898CAR-TOn-target off-tumor toxicityNormal tissueAnimal modelAdenovirus |
| spellingShingle | Qibin Liao Zhuoqun Liu Cuisong Zhu Huan He Meiqi Feng Lang Jiang Xiangqing Ding Rongxun Sun Xiaoyan Zhang Jianqing Xu 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 CAR-T On-target off-tumor toxicity Normal tissue Animal model Adenovirus |
| title | Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirus |
| title_full | Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirus |
| title_fullStr | Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirus |
| title_full_unstemmed | Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirus |
| title_short | Rapid generation of a mouse model for evaluating on-target normal tissue toxicity of human CAR-T cells using replication-defective recombinant adenovirus |
| title_sort | rapid generation of a mouse model for evaluating on target normal tissue toxicity of human car t cells using replication defective recombinant adenovirus |
| topic | CAR-T On-target off-tumor toxicity Normal tissue Animal model Adenovirus |
| url | http://www.sciencedirect.com/science/article/pii/S2090123222001898 |
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