Modified CD15/CD16-CLL1 inhibitory CAR-T cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemia
CLL1 Chimeric antigen receptor T-cell (CAR-T) therapy, as a promising immunotherapeutic approach, has demonstrated its potential to enhance the prognosis of patients diagnosed with acute myeloid leukemia (AML). However, due to the overexpression of CLL1 on neutrophils, CAR-T cells not only eliminate...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523324003516 |
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| author | Rui Zhang Yifan Zhao Xiao Chai Yingshuai Wang Mohan Zhao Shujing Guo Yu Zhang Mingfeng Zhao |
| author_facet | Rui Zhang Yifan Zhao Xiao Chai Yingshuai Wang Mohan Zhao Shujing Guo Yu Zhang Mingfeng Zhao |
| author_sort | Rui Zhang |
| collection | DOAJ |
| description | CLL1 Chimeric antigen receptor T-cell (CAR-T) therapy, as a promising immunotherapeutic approach, has demonstrated its potential to enhance the prognosis of patients diagnosed with acute myeloid leukemia (AML). However, due to the overexpression of CLL1 on neutrophils, CAR-T cells not only eliminated tumor cells but also eradicated neutrophils simultaneously, resulting in severe granulocytopenia and subsequent infections. Considering the distinct expression levels of CD15/CD16 on neutrophils and AML blasts, we have devised novel modified CD15 /CD16-CLL1 iCAR structures incorporating diverse inhibitory elements. Through extensive screening of structural optimization, we have successfully identified CD16-CLL1 iCAR-T cells that combine PD1 and 2B4 blockade, as well as a single VHH fragment replacing the entire CD16 scFv recognition domain. These modified cells demonstrate enhanced cytotoxicity against blasts while minimizing neutrophil elimination. Furthermore, their functionality has been effectively validated through both in vitro and in vivo experiments. In conclusion, we have successfully engineered innovative CD16-CLL1 iCAR-T cells, which preserves the cytotoxicity against tumor cells while preventing elimination of neutrophils, thereby significantly reducing the incidence of granulocytopenia during CAR-T therapy. Furthermore, our future objectives encompass the meticulous validation of both the efficacy and safety profile of this groundbreaking CAR-T therapy in clinical trials, as well as a comprehensive assessment of its potential to enhance the prognosis of patients diagnosed with AML. |
| format | Article |
| id | doaj-art-237592516d9541c18825a761bc50f45f |
| institution | Kabale University |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-237592516d9541c18825a761bc50f45f2025-01-22T05:41:23ZengElsevierTranslational Oncology1936-52332025-02-0152102225Modified CD15/CD16-CLL1 inhibitory CAR-T cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemiaRui Zhang0Yifan Zhao1Xiao Chai2Yingshuai Wang3Mohan Zhao4Shujing Guo5Yu Zhang6Mingfeng Zhao7Department of Hematology, Tianjin First Central Hospital, Tianjin 300380, ChinaThe First Central Clinical College of Tianjin Medical University, Tianjin 300380, ChinaThe First Central Clinical College of Tianjin Medical University, Tianjin 300380, ChinaDepartment of Internal Medicine III, University Hospital Munich, Ludwig-Maximilians-University, Munich, GermanyThe First Central Clinical College of Tianjin Medical University, Tianjin 300380, ChinaThe First Central Clinical College of Tianjin Medical University, Tianjin 300380, ChinaDepartment of Hematology, Tianjin First Central Hospital, Tianjin 300380, ChinaDepartment of Hematology, Tianjin First Central Hospital, Tianjin 300380, China; Corresponding author at: Department of Hematology, Tianjin First Central Hospital, No. 2 Baoshanxi Road, Xiqing District, Tianjin 300380, China.CLL1 Chimeric antigen receptor T-cell (CAR-T) therapy, as a promising immunotherapeutic approach, has demonstrated its potential to enhance the prognosis of patients diagnosed with acute myeloid leukemia (AML). However, due to the overexpression of CLL1 on neutrophils, CAR-T cells not only eliminated tumor cells but also eradicated neutrophils simultaneously, resulting in severe granulocytopenia and subsequent infections. Considering the distinct expression levels of CD15/CD16 on neutrophils and AML blasts, we have devised novel modified CD15 /CD16-CLL1 iCAR structures incorporating diverse inhibitory elements. Through extensive screening of structural optimization, we have successfully identified CD16-CLL1 iCAR-T cells that combine PD1 and 2B4 blockade, as well as a single VHH fragment replacing the entire CD16 scFv recognition domain. These modified cells demonstrate enhanced cytotoxicity against blasts while minimizing neutrophil elimination. Furthermore, their functionality has been effectively validated through both in vitro and in vivo experiments. In conclusion, we have successfully engineered innovative CD16-CLL1 iCAR-T cells, which preserves the cytotoxicity against tumor cells while preventing elimination of neutrophils, thereby significantly reducing the incidence of granulocytopenia during CAR-T therapy. Furthermore, our future objectives encompass the meticulous validation of both the efficacy and safety profile of this groundbreaking CAR-T therapy in clinical trials, as well as a comprehensive assessment of its potential to enhance the prognosis of patients diagnosed with AML.http://www.sciencedirect.com/science/article/pii/S1936523324003516CLL1Acute myeloid leukemiaGranulocytopeniaCAR-T |
| spellingShingle | Rui Zhang Yifan Zhao Xiao Chai Yingshuai Wang Mohan Zhao Shujing Guo Yu Zhang Mingfeng Zhao Modified CD15/CD16-CLL1 inhibitory CAR-T cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemia Translational Oncology CLL1 Acute myeloid leukemia Granulocytopenia CAR-T |
| title | Modified CD15/CD16-CLL1 inhibitory CAR-T cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemia |
| title_full | Modified CD15/CD16-CLL1 inhibitory CAR-T cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemia |
| title_fullStr | Modified CD15/CD16-CLL1 inhibitory CAR-T cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemia |
| title_full_unstemmed | Modified CD15/CD16-CLL1 inhibitory CAR-T cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemia |
| title_short | Modified CD15/CD16-CLL1 inhibitory CAR-T cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemia |
| title_sort | modified cd15 cd16 cll1 inhibitory car t cells for mitigating granulocytopenia toxicities in the treatment of acute myeloid leukemia |
| topic | CLL1 Acute myeloid leukemia Granulocytopenia CAR-T |
| url | http://www.sciencedirect.com/science/article/pii/S1936523324003516 |
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