Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy
Abstract Background For CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after treatment with murine CD19 (mCD19) CAR-T, the reinfusion of mCD19 CAR-T cells may be ineffective due to anti-mouse single-chain variable fragment (scFv) antibody caused by mCD19 CAR. To ov...
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| Format: | Article |
| Language: | English |
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BMC
2022-04-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-022-09489-1 |
| _version_ | 1818480664373100544 |
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| author | Lihong An Yuehui Lin Biping Deng Zhichao Yin Defeng Zhao Zhuojun Ling Tong Wu Yongqiang Zhao Alex H. Chang Chunrong Tong Shuangyou Liu |
| author_facet | Lihong An Yuehui Lin Biping Deng Zhichao Yin Defeng Zhao Zhuojun Ling Tong Wu Yongqiang Zhao Alex H. Chang Chunrong Tong Shuangyou Liu |
| author_sort | Lihong An |
| collection | DOAJ |
| description | Abstract Background For CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after treatment with murine CD19 (mCD19) CAR-T, the reinfusion of mCD19 CAR-T cells may be ineffective due to anti-mouse single-chain variable fragment (scFv) antibody caused by mCD19 CAR. To overcome this immunogenicity, we applied humanized CD19 (hCD19) CAR-T cells to treat r/r B-ALL patients with prior mCD19 CAR-T therapy. Methods Nineteen pediatric and adult patients were included, 16 relapsed after and 3 were primarily resistant to mCD19 CAR-T. All patients presented with more than 5% blasts in bone marrow and/or extramedullary disease, and still showed CD19 antigen expression. Humanized CD19-CARs were lentiviral vectors carrying a second generation CAR with 4–1-BB co-stimulatory and CD3ζ signaling domains. Patient-derived cells were collected for producing CAR-T cells, the median dose of infused hCD19 CAR-T cells was 2.4 × 105/kg (range, 1.0–18.0 × 105/kg). Results hCD19 CAR-T resulted in a complete remission (CR) rate of 68% (13/19). Among 13 remission patients, 11 underwent allogeneic hematopoietic cell transplantation (allo-HCT) (3 were second HCT) and 10 remained in CR; the event-free survival rates at 12–18 months were 91% in 11 patients received following allo-HCT and 69% in all CR patients. Six cases had no response to hCD19 CAR-T, 3 died of disease progression; another 3 received salvage second transplantation, of them, 2 relapsed again (one died). Cytokine release syndrome (CRS) occurred in 95% (18/19) of patients, most CRS events were grade 1 and grade 2 (n = 17), there was only one grade 4 CRS. Two cases experienced grade 1 neurotoxicity. Conclusions Humanized CD19 CAR-T cell therapy could be a treatment option for CD19-positive B-ALL patients who relapsed after or resisted prior murine CD19 CAR-T, hCD19 CAR-T followed by allo-HCT provided a longer remission in CR patients. Nevertheless, the prognosis of non-responders to hCD19 CAR-T remained dismal. Trial registration Chinese Clinical Trial Registry/WHO International Clinical Trial Registry ( ChiCTR1900024456 , URL: www.chictr.org.cn ); registered on July 12, 2019. |
| first_indexed | 2024-12-10T11:25:53Z |
| format | Article |
| id | doaj.art-a2fdeb5fa2514754859629de837f704e |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-10T11:25:53Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-a2fdeb5fa2514754859629de837f704e2022-12-22T01:50:45ZengBMCBMC Cancer1471-24072022-04-012211810.1186/s12885-022-09489-1Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapyLihong An0Yuehui Lin1Biping Deng2Zhichao Yin3Defeng Zhao4Zhuojun Ling5Tong Wu6Yongqiang Zhao7Alex H. Chang8Chunrong Tong9Shuangyou Liu10Department of Hematology, Beijing Boren HospitalDepartment of Hematology, Beijing Boren HospitalCytology Laboratory, Beijing Boren HospitalDepartment of Hematology, Beijing Boren HospitalDepartment of Hematology, Beijing Boren HospitalDepartment of Hematology, Beijing Boren HospitalDepartment of Hematopoietic Cell Transplantation, Beijing Boren HospitalDepartment of Hematopoietic Cell Transplantation, Beijing Boren HospitalClinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of MedicineDepartment of Hematology, Beijing Boren HospitalDepartment of Hematology, Beijing Boren HospitalAbstract Background For CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after treatment with murine CD19 (mCD19) CAR-T, the reinfusion of mCD19 CAR-T cells may be ineffective due to anti-mouse single-chain variable fragment (scFv) antibody caused by mCD19 CAR. To overcome this immunogenicity, we applied humanized CD19 (hCD19) CAR-T cells to treat r/r B-ALL patients with prior mCD19 CAR-T therapy. Methods Nineteen pediatric and adult patients were included, 16 relapsed after and 3 were primarily resistant to mCD19 CAR-T. All patients presented with more than 5% blasts in bone marrow and/or extramedullary disease, and still showed CD19 antigen expression. Humanized CD19-CARs were lentiviral vectors carrying a second generation CAR with 4–1-BB co-stimulatory and CD3ζ signaling domains. Patient-derived cells were collected for producing CAR-T cells, the median dose of infused hCD19 CAR-T cells was 2.4 × 105/kg (range, 1.0–18.0 × 105/kg). Results hCD19 CAR-T resulted in a complete remission (CR) rate of 68% (13/19). Among 13 remission patients, 11 underwent allogeneic hematopoietic cell transplantation (allo-HCT) (3 were second HCT) and 10 remained in CR; the event-free survival rates at 12–18 months were 91% in 11 patients received following allo-HCT and 69% in all CR patients. Six cases had no response to hCD19 CAR-T, 3 died of disease progression; another 3 received salvage second transplantation, of them, 2 relapsed again (one died). Cytokine release syndrome (CRS) occurred in 95% (18/19) of patients, most CRS events were grade 1 and grade 2 (n = 17), there was only one grade 4 CRS. Two cases experienced grade 1 neurotoxicity. Conclusions Humanized CD19 CAR-T cell therapy could be a treatment option for CD19-positive B-ALL patients who relapsed after or resisted prior murine CD19 CAR-T, hCD19 CAR-T followed by allo-HCT provided a longer remission in CR patients. Nevertheless, the prognosis of non-responders to hCD19 CAR-T remained dismal. Trial registration Chinese Clinical Trial Registry/WHO International Clinical Trial Registry ( ChiCTR1900024456 , URL: www.chictr.org.cn ); registered on July 12, 2019.https://doi.org/10.1186/s12885-022-09489-1Chimeric antigen receptor-TAcute lymphoblastic leukemiaRelapsed/refractorySingle-chain variable fragment |
| spellingShingle | Lihong An Yuehui Lin Biping Deng Zhichao Yin Defeng Zhao Zhuojun Ling Tong Wu Yongqiang Zhao Alex H. Chang Chunrong Tong Shuangyou Liu Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy BMC Cancer Chimeric antigen receptor-T Acute lymphoblastic leukemia Relapsed/refractory Single-chain variable fragment |
| title | Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy |
| title_full | Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy |
| title_fullStr | Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy |
| title_full_unstemmed | Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy |
| title_short | Humanized CD19 CAR-T cells in relapsed/refractory B-ALL patients who relapsed after or failed murine CD19 CAR-T therapy |
| title_sort | humanized cd19 car t cells in relapsed refractory b all patients who relapsed after or failed murine cd19 car t therapy |
| topic | Chimeric antigen receptor-T Acute lymphoblastic leukemia Relapsed/refractory Single-chain variable fragment |
| url | https://doi.org/10.1186/s12885-022-09489-1 |
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