Allogeneic CAR-T cells with of HLA-A/B and TRAC disruption exhibit promising antitumor capacity against B cell malignancies
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Published:2024-01
Issue:1
Volume:73
Page:
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ISSN:0340-7004
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Container-title:Cancer Immunology, Immunotherapy
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language:en
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Short-container-title:Cancer Immunol Immunother
Author:
Chen Xinfeng,Tan Binghe,Xing Haizhou,Zhao Xuan,Ping Yu,Zhang Zhen,Huang Jianmin,Shi Xiujuan,Zhang Na,Lin Boxu,Cao Weijie,Li Xin,Zhang Xudong,Li Ling,Jiang Zhongxing,Zhang Mingzhi,Li Wei,Liu Mingyao,Du Bing,Zhang Yi
Abstract
Abstract
Background
Although chimeric antigen receptor T (CAR-T) cells have been proven to be an effective way of treating B cell malignancies, a lot of patients could not benefit from it because of failure in CAR-T cell manufacturing, disease progression, and unaffordable price. The study aimed to explore universal CAR-T cell products to extend the clinical accessibility.
Methods
The antitumor activity of CRISPR/Cas9-edited allogeneic anti-CD19 CAR-T (CAR-T19) cells was assessed in vitro, in animal models, and in patients with relapsed/refractory (R/R) acute B cell lymphoblastic leukemia (B-ALL) or diffuse large B cell lymphoma.
Results
B2M−/TRAC− universal CAR-T19 (U-CAR-T19) cells exhibited powerful anti-leukemia abilities both in vitro and in animal models, as did primary CD19+ leukemia cells from leukemia patients. However, expansion, antitumor efficacy, or graft-versus-host-disease (GvHD) was not observed in six patients with R/R B cell malignancies after U-CAR-T19 cell infusion. Accordingly, significant activation of natural killer (NK) cells by U-CAR-T19 cells was proven both clinically and in vitro. HLA-A−/B−/TRAC− novel CAR-T19 (nU-CAR-T19) cells were constructed with similar tumoricidal capacity but resistance to NK cells in vitro. Surprisingly, robust expansion of nU-CAR-T19 cells, along with rapid eradication of CD19+ abnormal B cells, was observed in the peripheral blood and bone marrow of another three patients with R/R B-ALL. The patients achieved complete remission with no detectable minimal residual disease 14 days after the infusion of nU-CAR-T19 cells. Two of the three patients had grade 2 cytokine release syndrome, which were managed using an IL-6 receptor blocker. Most importantly, GvHD was not observed in any patient, suggesting the safety of TRAC-disrupted CAR-T cells generated using the CRISPR/Cas9 method for clinical application.
Conclusions
The nU-CAR-T19 cells showed a strong response in R/R B-ALL. nU-CAR-T19 cells have the potential to be a promising new approach for treating R/R B cell malignancies.
Funder
grants from the Healthy Talents Project of Henan Province the Key Project of Medical Science and Technology of Henan Province the Project of Central Leading Local Science and Technology Development of Henan Province
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology,Immunology,Immunology and Allergy
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