肿瘤细胞治疗研究
英文原题：Long-term outcomes of CNCT19 chimeric antigen receptor T-cell therapy in relapsed or refractory aggressive B-cell lymphoma.
CNCT19s 在复发/难治性弥漫大 B 细胞淋巴瘤（DLBCL）和 FL3B 患者中表现出良好的安全性和疗效。
背景：多数抗CD19嵌合抗原受体（CAR）T细胞产品使用源自FMC63单克隆抗体的单链可变片段（scFv）。我们开发了新杂交瘤克隆HI19，可结合CD19上的不同表位。CNCT19是一种第二代CAR-T细胞，其scFv源自HI19克隆，并含有4-1BB共刺激结构域。本研究开展一项初步临床试验，评估CNCT19细胞（CNCT19s）治疗复发或难治性（R/R）侵袭性B细胞淋巴瘤患者的安全性和初步疗效。 方法：2017年6月至2019年3月，血液病医院纳入16例R/R CD19阳性侵袭性B细胞淋巴瘤患者。所有患者在CNCT19s输注前接受淋巴清除化疗，包括氟达拉滨（第4、3、2天每日25–30 mg/m²）和环磷酰胺（第4和2天每日350 mg/m²）。主要研究目标为安全性特征。使用Kaplan-Meier生存分析比较累积发生率。 结果：研究队列包括14例新发弥漫大B细胞淋巴瘤（DLBCL）、1例3B级滤泡性淋巴瘤（FL3B）和1例Richter转化患者。既往治疗线数中位数为3线（范围1–7）。13例患者（81.3%）对最近一线治疗耐药，12例中5例（41.7%）检测到TP53突变和/或缺失。CNCT19s中位输注剂量为3.6×10^6/kg（范围1.8–6.5×10^6/kg）。11例（68.8%）发生CRS，均为1级。1例患者（6.3%）发生CAR-T相关脑病综合征。总缓解率和完全缓解率分别为75%（12/16）和43.8%（7/16）。中位随访54.0个月后，估算的5年无进展生存率和总生存率分别为25.0%和37.5%。 结论：CNCT19s治疗R/R DLBCL和FL3B患者安全性良好且有效。长期随访确认CNCT19s治疗R/R侵袭性B细胞淋巴瘤具有治愈潜力。 试验注册：ClinicalTrials.gov，NCT03029338。
BACKGROUND: Most anti-CD19 chimeric antigen receptor (CAR) T-cell products have the single-chain variable fragment (scFv) derived from the FMC63 monoclonal antibody. We developed a new hybridoma clone, HI19 , which binds to distinct epitopes on CD19. CNCT19 is a second-generation CAR T-cell with a scFv derived from clone HI19 and a 4-1BB costimulatory domain. A pilot clinical trial was conducted to assess the safety and preliminary efficacy of CNCT19 cells (CNCT19s) in patients with relapsed or refractory (R/R) aggressive B-cell lymphoma. METHODS: From June 2017 to March 2019, 16 patients with R/R CD19-positive aggressive B-cell lymphoma from the Institute of Hematology and Blood Disease Hospital were enrolled. All patients received lymphodepleting chemotherapy with fludarabine (25-30 mg/m 2 /per day on days 4, 3, and 2) and cyclophosphamide (350 mg/m 2 /per day on days 4 and 2) before CNCT19s infusion. The primary objective was the safety profiles. Kaplan-Meier survival analysis was used to compare the cumulative incidence rate. RESULTS: The study cohort comprised 14 patients diagnosed with de novo diffuse large B-cell lymphoma (DLBCL), one patient with follicular lymphoma grade 3B (FL3B), and one patient with Richter's transformation. The patients had received a median of 3 (range 1-7) lines of prior therapy. Thirteen patients (81.3%) had disease resistant to the last-line therapy, and TP53 mutation and/or deletion were detected in 5 of 12 patients (41.7%). The median dose of CNCT19s infusion was 3.6 10 6 (range 1.8-6.5 10 6 )/kg. Cytokine release syndrome occurred in 11 (68.8%) patients, all classified as grade 1. One patient (6.3%) experienced CAR T-cell-related encephalopathy syndrome. The overall response rate and the complete response rate were 75% (12/16) and 43.8% (7/16), respectively. After a median follow-up of 54.0 months, the estimated 5-year progression-free survival and overall survival rates were 25.0% and 37.5%, respectively. CONCLUSIONS: CNCT19s exhibited favorable safety profiles and efficacy in patients with R/R DLBCL and FL3B. Long-term follow-up confirmed the curative potential of CNCT19s in R/R aggressive B-cell lymphoma. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03029338.
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