A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia

Autor: Jianyu Weng, Peilong Lai, Le Qin, Yunxin Lai, Zhiwu Jiang, Chenwei Luo, Xin Huang, Suijing Wu, Dan Shao, Chengxin Deng, Lisi Huang, Zesheng Lu, Maohua Zhou, Lingji Zeng, Dongmei Chen, Yulian Wang, Xiaomei Chen, Suxia Geng, Weinkove Robert, Zhaoyang Tang, Chang He, Peng Li, Xin Du
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Journal of Hematology & Oncology, Vol 11, Iss 1, Pp 1-12 (2018)
Druh dokumentu: article
ISSN: 1756-8722
DOI: 10.1186/s13045-018-0572-x
Popis: Abstract Background Anti-CD19 chimeric antigen receptor (CAR) T cells have shown promise in the treatment of B cell acute lymphocytic leukemia (B-ALL). However, its efficacy in B-ALL patients with extramedullary involvement is limited due to poor responses and neurotoxicity. Here, we utilized a third generation of CAR T cell vector, which contains the Toll/interleukin-1 receptor (ITR) domain of Toll-like receptor 2 (TLR2), to generate 1928zT2 T cells targeting CD19, and evaluated the efficacy of 1928zT2 T cells in relapse or refractory B-ALL patients with extramedullary involvement. Methods 1928zT2 T cells were generated by 19-28z-TLR2 lentiviral vector transfection into primary human T lymphocytes. The anti-leukemia effect of 1928zT2 T cells were determined by killing assays and in xenografts. Three patients diagnosed as relapse or refractory ALL with extramedullary involvement were infused with 1928zT2 T cells, and the clinical responses were evaluated by BM smear, B-ultrasonography, PET/CT, histology, flow cytometry, qPCR, ELISA, and luminex assay. Results 1928zT2 T cells exhibited enhanced effector function against CD19+ leukemic cells in vitro and in a xenograft model of human extramedullary leukemia. Notably, the 1928zT2 T cells eradicated extramedullary leukemia and induced complete remission in the three relapse and refractory ALL patients without serious adverse effects. 1928zT2 T cells expanded robustly in the circulation of these three patients and were detected in the cerebrospinal fluid of patient 3. These three patients experienced cytokine release syndrome (CRS) with grade 2 or 3, which remitted spontaneously or after tocilizumab treatment. None of the three patients suffered neurotoxicity or needed further intensive care. Conclusions Our results demonstrate that 1928zT2 T cells with TLR2 incorporation augment anti-leukemic effects, particularly for eradicating extramedullary leukemia cells, and suggest that the infusion of 1928zT2 T cells is an encouraging treatment for relapsed/refractory ALL patients with extramedullary involvement. Trial registration ClinicalTrials.gov identifier NCT02822326. Date of registration: July 4, 2016.
Databáze: Directory of Open Access Journals
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