Efficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trial
Abstract Background Third‑generation CAR-T cells demonstrated promising efficacy and remarkably low toxicity in refractory or relapsed (R/R) B-cell malignancies. However, data on the patients with central nervous system (CNS) involvement are limited due to concerns regarding treatment-related neurot...
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BMC
2025-05-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06608-x |
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| author | Bailin He Ren Lin Na Xu Le Qin Zhixiang Wang Qiang Wang Xiaofang Li Xiaolei Wei Yongqiang Wei Zhaoyang Tang Zhiping Fan Fen Huang Xiaoli Liu Jing Sun Li Xuan Peng Li Hongsheng Zhou Qifa Liu |
| author_facet | Bailin He Ren Lin Na Xu Le Qin Zhixiang Wang Qiang Wang Xiaofang Li Xiaolei Wei Yongqiang Wei Zhaoyang Tang Zhiping Fan Fen Huang Xiaoli Liu Jing Sun Li Xuan Peng Li Hongsheng Zhou Qifa Liu |
| author_sort | Bailin He |
| collection | DOAJ |
| description | Abstract Background Third‑generation CAR-T cells demonstrated promising efficacy and remarkably low toxicity in refractory or relapsed (R/R) B-cell malignancies. However, data on the patients with central nervous system (CNS) involvement are limited due to concerns regarding treatment-related neurotoxicity. This study aimed to evaluate the safety and efficacy of a novel third-generation anti-CD19 CAR T cells in patients with CNS involvement of B-cell malignancies. Methods A total of 21 patients with R/R B-cell malignancies with CNS involvement, including 11 with B-cell acute lymphoblastic leukemia (B-ALL) and 10 with B-cell non-Hodgkin lymphoma (B-NHL) were enrolled. Patients derived lymphocytes were collected through apheresis and lentivirally transduced with the third-generation CAR incorporating both CD28 co-stimulation and TLR2-derived stimulatory domains (1928zT2). Patients received a single-dose 1928zT2 CAR-T cell infusion following lymphodepleting regimen. Safety, efficacy and cellular pharmacokinetics were investigated. Results Of the 21 patients with CNS involvement, the overall response rate (ORR) was 71% (15/21), with 73% (8/11) in B-ALL and 70% (7/10) in B-NHL. At a median follow-up of 20.4 months, median duration of response (DOR) was 11.1 months (95% CI, 2.9–24.4). 12-months progression-free survival (PFS) and overall survival (OS) estimates were 41.5% and 61.2%, respectively. Cytokine release syndrome (CRS) of any grade occurred in 20 patients (95%; grade ≥ 3 in 3 patients). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9 patients (42.8%; grade ≥ 3 in 6 patients). All CRS and ICANS events were manageable. The outcomes and adverse events are comparable between B-ALL and B-NHL patients. Notably, 1928zT2 CAR-T cells demonstrated blood–brain barrier penetrance, with subsequent detection in patient cerebrospinal fluid (CSF) correlating significantly with improved clinical outcomes. Conclusions Third-generation 1928zT2 CAR-T cells are associated with high response rates, manageable safety and durable remissions in R/R B-cell malignancies with CNS involvement. Trial registration: ClinicalTrials.gov, NCT04605666. Registered 1 May 2020. |
| format | Article |
| id | doaj-art-a898a6fa1a754cd19c2d965b5cf8d69e |
| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| spelling | doaj-art-a898a6fa1a754cd19c2d965b5cf8d69e2025-08-20T02:03:38ZengBMCJournal of Translational Medicine1479-58762025-05-0123111210.1186/s12967-025-06608-xEfficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trialBailin He0Ren Lin1Na Xu2Le Qin3Zhixiang Wang4Qiang Wang5Xiaofang Li6Xiaolei Wei7Yongqiang Wei8Zhaoyang Tang9Zhiping Fan10Fen Huang11Xiaoli Liu12Jing Sun13Li Xuan14Peng Li15Hongsheng Zhou16Qifa Liu17Department of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityChina-New Zealand Joint Laboratory On Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityGuangdong Zhaotai InVivo Biomedicine Co., Ltd.Department of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityChina-New Zealand Joint Laboratory On Biomedicine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Key Laboratory of Immune Response and Immunotherapy, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityDepartment of Hematology, Nanfang Hospital, Southern Medical UniversityAbstract Background Third‑generation CAR-T cells demonstrated promising efficacy and remarkably low toxicity in refractory or relapsed (R/R) B-cell malignancies. However, data on the patients with central nervous system (CNS) involvement are limited due to concerns regarding treatment-related neurotoxicity. This study aimed to evaluate the safety and efficacy of a novel third-generation anti-CD19 CAR T cells in patients with CNS involvement of B-cell malignancies. Methods A total of 21 patients with R/R B-cell malignancies with CNS involvement, including 11 with B-cell acute lymphoblastic leukemia (B-ALL) and 10 with B-cell non-Hodgkin lymphoma (B-NHL) were enrolled. Patients derived lymphocytes were collected through apheresis and lentivirally transduced with the third-generation CAR incorporating both CD28 co-stimulation and TLR2-derived stimulatory domains (1928zT2). Patients received a single-dose 1928zT2 CAR-T cell infusion following lymphodepleting regimen. Safety, efficacy and cellular pharmacokinetics were investigated. Results Of the 21 patients with CNS involvement, the overall response rate (ORR) was 71% (15/21), with 73% (8/11) in B-ALL and 70% (7/10) in B-NHL. At a median follow-up of 20.4 months, median duration of response (DOR) was 11.1 months (95% CI, 2.9–24.4). 12-months progression-free survival (PFS) and overall survival (OS) estimates were 41.5% and 61.2%, respectively. Cytokine release syndrome (CRS) of any grade occurred in 20 patients (95%; grade ≥ 3 in 3 patients). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 9 patients (42.8%; grade ≥ 3 in 6 patients). All CRS and ICANS events were manageable. The outcomes and adverse events are comparable between B-ALL and B-NHL patients. Notably, 1928zT2 CAR-T cells demonstrated blood–brain barrier penetrance, with subsequent detection in patient cerebrospinal fluid (CSF) correlating significantly with improved clinical outcomes. Conclusions Third-generation 1928zT2 CAR-T cells are associated with high response rates, manageable safety and durable remissions in R/R B-cell malignancies with CNS involvement. Trial registration: ClinicalTrials.gov, NCT04605666. Registered 1 May 2020.https://doi.org/10.1186/s12967-025-06608-xCAR T cell therapyB-cell malignanciesCentral nervous system involvementThird-generation CARTLR2 co-stimulation |
| spellingShingle | Bailin He Ren Lin Na Xu Le Qin Zhixiang Wang Qiang Wang Xiaofang Li Xiaolei Wei Yongqiang Wei Zhaoyang Tang Zhiping Fan Fen Huang Xiaoli Liu Jing Sun Li Xuan Peng Li Hongsheng Zhou Qifa Liu Efficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trial Journal of Translational Medicine CAR T cell therapy B-cell malignancies Central nervous system involvement Third-generation CAR TLR2 co-stimulation |
| title | Efficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trial |
| title_full | Efficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trial |
| title_fullStr | Efficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trial |
| title_full_unstemmed | Efficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trial |
| title_short | Efficacy and safety of third-generation CD19-CAR T cells incorporating CD28 and TLR2 intracellular domains for B-cell malignancies with central nervous system involvement: results of a pivotal trial |
| title_sort | efficacy and safety of third generation cd19 car t cells incorporating cd28 and tlr2 intracellular domains for b cell malignancies with central nervous system involvement results of a pivotal trial |
| topic | CAR T cell therapy B-cell malignancies Central nervous system involvement Third-generation CAR TLR2 co-stimulation |
| url | https://doi.org/10.1186/s12967-025-06608-x |
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