Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma
Abstract Background T cell receptor (TCR)-T cells possess similar effector function, but milder and more durable signal activation compared with chimeric antigen receptor-T cells. TCR-T cell therapy is another active field of cellular immunotherapy for cancer. Methods We previously developed a human...
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| Format: | Article |
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BMC
2023-01-01
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| Series: | Journal of Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13045-023-01402-y |
| _version_ | 1797945721879527424 |
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| author | Chenggong Li Fen Zhou Jing Wang Qi Chang Mengyi Du Wenjing Luo Yinqiang Zhang Jia Xu Lu Tang Huiwen Jiang Lin Liu Haiming Kou Cong Lu Danying Liao Jianghua Wu Qiuzhe Wei Sha Ke Jun Deng Cheng Liu Heng Mei Yu Hu |
| author_facet | Chenggong Li Fen Zhou Jing Wang Qi Chang Mengyi Du Wenjing Luo Yinqiang Zhang Jia Xu Lu Tang Huiwen Jiang Lin Liu Haiming Kou Cong Lu Danying Liao Jianghua Wu Qiuzhe Wei Sha Ke Jun Deng Cheng Liu Heng Mei Yu Hu |
| author_sort | Chenggong Li |
| collection | DOAJ |
| description | Abstract Background T cell receptor (TCR)-T cells possess similar effector function, but milder and more durable signal activation compared with chimeric antigen receptor-T cells. TCR-T cell therapy is another active field of cellular immunotherapy for cancer. Methods We previously developed a human anti-CD19 antibody (ET190L1) and generated novel CD19-specific γ/δ TCR-T cells, ET019003, by fusing the Fab fragment of ET190L1 with γ/δ TCR constant chain plus adding an ET190L1-scFv/CD28 co-stimulatory molecule. ET019003 cells were tested in preclinical studies followed by a phase 1 clinical trial. Results ET019003 cells produced less cytokines but retained comparable antitumor potency than ET190L1-CAR-T cells in vivo and in vitro. In the first-in-human trial, eight patients with relapsed or refractory DLBCL were treated. CRS of grade 1 was observed in three (37.5%) patients; ICANS of grade 3 was noted in one (12.5%) patient. Elevation of serum cytokines after ET019003 infusion was almost modest. With a median follow-up of 34 (range 6–38) months, seven (87.5%) patients attained clinical responses and six (75%) achieved complete responses (CR). OS, PFS and DOR at 3 years were 75.0%, 62.5%, and 71.4%, respectively. Notably, patient 1 with primary CNS lymphoma did not experience CRS or ICANS and got an ongoing CR for over 3 years after infusion, with detectable ET019003 cells in CSF. ET019003 showed striking in vivo expansion and persisted in 50% of patients at 12 months. Three patients received a second infusion, one for consolidation therapy after CR and two for salvage therapy after disease progression, but no response was observed. ET019003 expansion was striking in the first infusion, but poor in the second infusion. Conclusions CD19-specific γ/δ TCR-T cells, ET019003, had a good safety profile and could induce rapid responses and durable CR in patients with relapsed or refractory DLBCL, even primary CNS lymphoma, presenting a novel and potent therapeutic option for these patients. Trial registration: NCT04014894. |
| first_indexed | 2024-04-10T20:59:36Z |
| format | Article |
| id | doaj.art-1fb88f480e6b4b3cb4bb6aee4ffc3b91 |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-04-10T20:59:36Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-1fb88f480e6b4b3cb4bb6aee4ffc3b912023-01-22T12:22:41ZengBMCJournal of Hematology & Oncology1756-87222023-01-0116111510.1186/s13045-023-01402-yNovel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphomaChenggong Li0Fen Zhou1Jing Wang2Qi Chang3Mengyi Du4Wenjing Luo5Yinqiang Zhang6Jia Xu7Lu Tang8Huiwen Jiang9Lin Liu10Haiming Kou11Cong Lu12Danying Liao13Jianghua Wu14Qiuzhe Wei15Sha Ke16Jun Deng17Cheng Liu18Heng Mei19Yu Hu20Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyHubei Clinical Medical Center of Cell Therapy for Neoplastic DiseaseDepartment of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyEureka Therapeutics, IncInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyEureka Therapeutics, IncInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInstitute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background T cell receptor (TCR)-T cells possess similar effector function, but milder and more durable signal activation compared with chimeric antigen receptor-T cells. TCR-T cell therapy is another active field of cellular immunotherapy for cancer. Methods We previously developed a human anti-CD19 antibody (ET190L1) and generated novel CD19-specific γ/δ TCR-T cells, ET019003, by fusing the Fab fragment of ET190L1 with γ/δ TCR constant chain plus adding an ET190L1-scFv/CD28 co-stimulatory molecule. ET019003 cells were tested in preclinical studies followed by a phase 1 clinical trial. Results ET019003 cells produced less cytokines but retained comparable antitumor potency than ET190L1-CAR-T cells in vivo and in vitro. In the first-in-human trial, eight patients with relapsed or refractory DLBCL were treated. CRS of grade 1 was observed in three (37.5%) patients; ICANS of grade 3 was noted in one (12.5%) patient. Elevation of serum cytokines after ET019003 infusion was almost modest. With a median follow-up of 34 (range 6–38) months, seven (87.5%) patients attained clinical responses and six (75%) achieved complete responses (CR). OS, PFS and DOR at 3 years were 75.0%, 62.5%, and 71.4%, respectively. Notably, patient 1 with primary CNS lymphoma did not experience CRS or ICANS and got an ongoing CR for over 3 years after infusion, with detectable ET019003 cells in CSF. ET019003 showed striking in vivo expansion and persisted in 50% of patients at 12 months. Three patients received a second infusion, one for consolidation therapy after CR and two for salvage therapy after disease progression, but no response was observed. ET019003 expansion was striking in the first infusion, but poor in the second infusion. Conclusions CD19-specific γ/δ TCR-T cells, ET019003, had a good safety profile and could induce rapid responses and durable CR in patients with relapsed or refractory DLBCL, even primary CNS lymphoma, presenting a novel and potent therapeutic option for these patients. Trial registration: NCT04014894.https://doi.org/10.1186/s13045-023-01402-yγ/δ TCR-T cellsDLBCLPrimary CNS lymphomaRelapsed or refractoryCellular immunotherapy |
| spellingShingle | Chenggong Li Fen Zhou Jing Wang Qi Chang Mengyi Du Wenjing Luo Yinqiang Zhang Jia Xu Lu Tang Huiwen Jiang Lin Liu Haiming Kou Cong Lu Danying Liao Jianghua Wu Qiuzhe Wei Sha Ke Jun Deng Cheng Liu Heng Mei Yu Hu Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma Journal of Hematology & Oncology γ/δ TCR-T cells DLBCL Primary CNS lymphoma Relapsed or refractory Cellular immunotherapy |
| title | Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma |
| title_full | Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma |
| title_fullStr | Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma |
| title_full_unstemmed | Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma |
| title_short | Novel CD19-specific γ/δ TCR-T cells in relapsed or refractory diffuse large B-cell lymphoma |
| title_sort | novel cd19 specific γ δ tcr t cells in relapsed or refractory diffuse large b cell lymphoma |
| topic | γ/δ TCR-T cells DLBCL Primary CNS lymphoma Relapsed or refractory Cellular immunotherapy |
| url | https://doi.org/10.1186/s13045-023-01402-y |
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