Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy
Abstract Background Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy against both B-cell malignancies and some types of solid tumors. Interleukin (IL) -15 is an important immune stimulator that may provide ideal long-term persistent CAR-T cells. However, higher bas...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-09-01
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| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-022-03626-x |
| _version_ | 1818026141177348096 |
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| author | Ying Zhang Qinghui Zhuang Fang Wang Can Zhang Chang Xu Aiqin Gu William H. Zhong Yi Hu Xiaosong Zhong |
| author_facet | Ying Zhang Qinghui Zhuang Fang Wang Can Zhang Chang Xu Aiqin Gu William H. Zhong Yi Hu Xiaosong Zhong |
| author_sort | Ying Zhang |
| collection | DOAJ |
| description | Abstract Background Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy against both B-cell malignancies and some types of solid tumors. Interleukin (IL) -15 is an important immune stimulator that may provide ideal long-term persistent CAR-T cells. However, higher base line or peak serum IL-15 levels are also related to severe toxicity, such as cytokine release syndrome (CRS), graft-versus-host disease (GVHD), and neurotoxicity. Methods We successfully constructed CD19 specific armored CAR-T cells overexpressing IL-I5 and IL-15 receptor alpha (IL-15Ra). In vitro cell differentiation and viability were monitored by flow cytometry, and an in vivo xenograft mouse models was used to evaluate the anti-tumor efficiency and liver damage of CAR-T cells. Results CAR-T cells overexpressing IL-15 alone demonstrated enhanced viability, retarded exhaustion in vitro and superior tumor-inhibitory effects in vivo. However, these tumor-free mice had lower survival rates, with serious liver injuries, as a possible result of toxicity. As expected, CAR-T cells overexpressing IL-15 combined with IL-15Ra had reduced CD132 expression and released fewer cytokines (IFNγ, IL-2 and IL-15) in vitro, as well as had the tendency to improve mouse survival via repressing the growth of tumor cells and keeping livers healthier compared to CAR-IL-15 T cells. Conclusions These results indicated the importance of IL-15 in enhancing T cells persistence and IL-15Ra in reducing the adverse effects of IL-15, with superior tumor retardation during CAR-T therapy. This study paves the way for the rapid exploitation of IL-15 in adoptive cell therapy in the future. |
| first_indexed | 2024-12-10T04:27:17Z |
| format | Article |
| id | doaj.art-4ef6982a9f5e49559aef7b354b47f000 |
| institution | Directory Open Access Journal |
| issn | 1479-5876 |
| language | English |
| last_indexed | 2024-12-10T04:27:17Z |
| publishDate | 2022-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj.art-4ef6982a9f5e49559aef7b354b47f0002022-12-22T02:02:15ZengBMCJournal of Translational Medicine1479-58762022-09-0120111310.1186/s12967-022-03626-xCo-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapyYing Zhang0Qinghui Zhuang1Fang Wang2Can Zhang3Chang Xu4Aiqin Gu5William H. ZhongYi Hu6Xiaosong Zhong7The Clinical Center of Gene and Cell Engineering, Beijing Shijitan Hospital, Capital Medical University, Haidian DistrictThe Clinical Center of Gene and Cell Engineering, Beijing Shijitan Hospital, Capital Medical University, Haidian DistrictThe Clinical Center of Gene and Cell Engineering, Beijing Shijitan Hospital, Capital Medical University, Haidian DistrictThe Clinical Center of Gene and Cell Engineering, Beijing Shijitan Hospital, Capital Medical University, Haidian DistrictThe Clinical Center of Gene and Cell Engineering, Beijing Shijitan Hospital, Capital Medical University, Haidian DistrictThe Clinical Center of Gene and Cell Engineering, Beijing Shijitan Hospital, Capital Medical University, Haidian DistrictThe Clinical Center of Gene and Cell Engineering, Beijing Shijitan Hospital, Capital Medical University, Haidian DistrictThe Clinical Center of Gene and Cell Engineering, Beijing Shijitan Hospital, Capital Medical University, Haidian DistrictAbstract Background Chimeric antigen receptor (CAR)-T cell therapy is a powerful adoptive immunotherapy against both B-cell malignancies and some types of solid tumors. Interleukin (IL) -15 is an important immune stimulator that may provide ideal long-term persistent CAR-T cells. However, higher base line or peak serum IL-15 levels are also related to severe toxicity, such as cytokine release syndrome (CRS), graft-versus-host disease (GVHD), and neurotoxicity. Methods We successfully constructed CD19 specific armored CAR-T cells overexpressing IL-I5 and IL-15 receptor alpha (IL-15Ra). In vitro cell differentiation and viability were monitored by flow cytometry, and an in vivo xenograft mouse models was used to evaluate the anti-tumor efficiency and liver damage of CAR-T cells. Results CAR-T cells overexpressing IL-15 alone demonstrated enhanced viability, retarded exhaustion in vitro and superior tumor-inhibitory effects in vivo. However, these tumor-free mice had lower survival rates, with serious liver injuries, as a possible result of toxicity. As expected, CAR-T cells overexpressing IL-15 combined with IL-15Ra had reduced CD132 expression and released fewer cytokines (IFNγ, IL-2 and IL-15) in vitro, as well as had the tendency to improve mouse survival via repressing the growth of tumor cells and keeping livers healthier compared to CAR-IL-15 T cells. Conclusions These results indicated the importance of IL-15 in enhancing T cells persistence and IL-15Ra in reducing the adverse effects of IL-15, with superior tumor retardation during CAR-T therapy. This study paves the way for the rapid exploitation of IL-15 in adoptive cell therapy in the future.https://doi.org/10.1186/s12967-022-03626-xArmored chimeric antigen receptor TInterleukin 15Interleukin 15 receptor alphaToxicity |
| spellingShingle | Ying Zhang Qinghui Zhuang Fang Wang Can Zhang Chang Xu Aiqin Gu William H. Zhong Yi Hu Xiaosong Zhong Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy Journal of Translational Medicine Armored chimeric antigen receptor T Interleukin 15 Interleukin 15 receptor alpha Toxicity |
| title | Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy |
| title_full | Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy |
| title_fullStr | Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy |
| title_full_unstemmed | Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy |
| title_short | Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy |
| title_sort | co expression il 15 receptor alpha with il 15 reduces toxicity via limiting il 15 systemic exposure during car t immunotherapy |
| topic | Armored chimeric antigen receptor T Interleukin 15 Interleukin 15 receptor alpha Toxicity |
| url | https://doi.org/10.1186/s12967-022-03626-x |
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