Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China.
J Hematol Oncol. 2018 Feb 20;11(1):25. doi: 10.1186/s13045-018-0572-x.
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.
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.
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.
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.
ClinicalTrials.gov identifier NCT02822326 . Date of registration: July 4, 2016.
嵌合抗原受体（CAR）T 细胞抗 CD19 在治疗 B 细胞急性淋巴细胞白血病（B-ALL）方面显示出了前景。然而，由于反应不佳和神经毒性，其在伴有髓外累及的 B-ALL 患者中的疗效受到限制。在这里，我们利用第三代 CAR T 细胞载体，该载体包含 Toll/白细胞介素-1 受体（ITR）域的 Toll 样受体 2（TLR2），生成靶向 CD19 的 1928zT2 T 细胞，并评估了 1928zT2 T 细胞在伴有髓外累及的复发或难治性 B-ALL 患者中的疗效。
通过 19-28z-TLR2 慢病毒载体转染原代人 T 淋巴细胞生成 1928zT2 T 细胞。通过杀伤试验和异种移植评估 1928zT2 T 细胞的抗白血病作用。三名诊断为伴有髓外累及的复发或难治性 ALL 的患者输注 1928zT2 T 细胞，通过 BM 涂片、B 超、PET/CT、组织学、流式细胞术、qPCR、ELISA 和 Luminex 检测评估临床反应。
1928zT2 T 细胞在体外和人髓外白血病异种移植模型中显示出对 CD19+白血病细胞的增强效应功能。值得注意的是，1928zT2 T 细胞消除了髓外白血病，并使 3 名复发和难治性 ALL 患者完全缓解，没有严重的不良反应。1928zT2 T 细胞在这 3 名患者的循环中大量扩增，并在患者 3 的脑脊液中检测到。这 3 名患者出现细胞因子释放综合征（CRS），等级为 2 级或 3 级，在未经治疗或经托珠单抗治疗后自行缓解。这 3 名患者均未出现神经毒性或需要进一步重症监护。
我们的结果表明，含有 TLR2 的 1928zT2 T 细胞增强了抗白血病作用，特别是消除髓外白血病细胞，提示输注 1928zT2 T 细胞是治疗伴有髓外累及的复发/难治性 ALL 患者的一种有前途的治疗方法。
ClinicalTrials.gov 标识符 NCT02822326。注册日期：2016 年 7 月 4 日。
