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

作者:Weng, Jianyu; Lai, Peilong; Qin, Le; Lai, Yunxin; Jiang, Zhiwu; Luo, Chenwei; Huang, Xin; Wu, Suijing; Shao, Dan; Deng, Chengxin; Huang, Lisi; Lu, Zesheng; Zhou, Maohua; Zeng, Lingji; Chen, Dongmei; Wang, Yulian; Chen, Xiaomei; Geng, Suxia; Robert, Weinkove; Tang, Zhaoyang; He, Chang; Li, Peng*; Du, Xin*
来源:Journal of Hematology & Oncology, 2018, 11(1): 25.
DOI:10.1186/s13045-018-0572-x

摘要

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.