Objective: To observe the local reactions and efficacy of CD19 CAR-T therapy in recurrence/refractory B-cell non-Hodgkin's lymphoma (R/R NHL) patients with >7.5 cm lesions. Methods: 32 R/R NHL patients with >7.5 cm lesions were enrolled and injected with CD19 CAR-T cells. Flow cytometry was used to detect and observe the amplification of CD19 CAR-T cells in vivo. Enzyme-linked immunosorbent assay (ELISA) was used to detect cytokines in peripheral blood of patients. The side effects of CD19 CAR-T cell therapy included systemic side effects and local reactions of tumor. The local side effects were observed by Ultrasound, Computed tomography and Magnetic resonance imaging. Treatment options included glucocorticoid, interleukin-6 antibody and drainage of exudate. Overall response rate (ORR) and overall survival rate (OS) were observed. Results: ①Among the 32 patients, CR (40.63%) , PR (31.25%) and ORR (71.88%) were 13, 10 and 23, respectively. ②In all 23 patients received ORR, 13 patients had grade 1-2 CRS, while 10 patients had grade 3-4 CRS. All the 9 patients in the SD+PD group had grade 1-2 CRS (P=0.030) . ③A total of 15 patients with tumor local reactions, included 9 patients with CR, 5 patients with PR and 1 patient with SD. The local reactions of the tumor included that the diameter of the superficial lesions increased with redness, swelling and heat pain. The deep lesions presented abdominal pain, abdominal distension, suffocation and local pain, and burning of the tumor. The deep lesions were enlarged or accompanied by local edema. The local exudative lesions were found in the abdominal cavity and pleural cavity. ④ Peak proportion of CD19 CAR-T cells in ORR group was higher than that of in SD+PD group[16.8% (5.3%-48.2%) vs 2.9% (1.5%-5.7%) , z=-4.297, P<0.001]. The peak proportion of CD19 CAR-T cells in ORR group with local reactions was higher than that of in patients without local reactions [22.2% (10.5%-48.2%) vs 12.6% (5.3%-21.6%) , z=-3.213, P=0.001]. The peak proportion of CD19 CAR-T cells in multiple lesion group was higher than that of in single lesion group [35.8% (1.5%-48.2%) vs 16.8% (10.5%-18.5%) , z=-2.023, P=0.040]. ⑤Occurrence of local reactions and tumor shrinkage time were both delayed compared with systemic side effects. ⑥In the ORR group, the OS of patients with tumor local reactions was longer than that of patients without tumor local reactions, but there was no difference in the two groups (75% vs 34.6%, P=0.169) . Conclusions: CD19 CAR-T cell therapy in R/R NHL patients with >7.5 cm lesions might cause tumor local reactions later than systemic side effects. Clinicaltrial:: ChiCTR1800018059.
目的： 观察病灶>7.5 cm的复发/难治B细胞非霍奇金淋巴瘤（R/R NHL）患者CD19嵌合抗原受体T细胞（CAR-T细胞）治疗的肿瘤局部反应及疗效。 方法： 以2018年8月至2020年5月接受CD19 CAR-T细胞治疗的病灶>7.5 cm的32例R/R NHL患者为研究对象，流式细胞仪检测CD19 CAR-T细胞的体内扩增情况；酶联免疫吸附测定法检测患者外周血中细胞因子水平；观察全身不良反应及肿瘤局部反应，分析总有效率（ORR）及总生存（OS）情况。 结果： ① 32例患者CAR-T细胞治疗后，13例获得完全缓解（CR）（40.63%），10例获得部分缓解（PR）（31.25%），ORR为71.88%。② 23例有效患者均发生细胞因子释放综合征（CRS），其中1~2级13例，3~4级10例；而疾病稳定+疾病进展（SD+PD）组9例患者CRS均为1~2级（P=0.030）。③共15例（46.9%）患者发生肿瘤局部反应，其中CR 9例、PR 5例、SD 1例，肿瘤局部反应包括：浅表肿物直径增大且伴红肿热痛；深部肿物表现为腹痛、腹胀、憋气以及肿瘤局部疼痛、烧灼，瘤体增大或伴局部水肿；肿瘤局部出现渗出性病变，可见于腹腔、胸膜腔等。④有效组CD19 CAR-T细胞峰值高于SD+PD组[16.8%（5.3%~48.2%）对2.9%（1.5%~5.7%），z=-4.297，P<0.001]，有效组中出现肿瘤局部反应患者CD19 CAR-T细胞峰值高于未出现肿瘤局部反应患者[22.2%（10.5%~48.2%）对12.6%（5.3%~21.6%），z=-3.213，P=0.001]，多发肿块组CD19 CAR-T细胞峰值高于单发肿块组[35.8%（1.5%~48.2%）对16.8%（10.5%~18.5%），z=-2.023，P=0.040]。⑤肿瘤局部反应出现和瘤体缩小时间，均较全身不良反应时间延迟。⑥有效患者中出现肿瘤局部反应者OS率高于未出现肿瘤局部反应者，但差异无统计学意义（75.0%对34.6%，P=0.169）。 结论： 病灶>7.5 cm的R/R NHL患者CD19 CAR-T细胞治疗，近一半出现肿瘤局部反应，发生时间迟于全身不良反应开始的时间。 临床试验注册：： 中国临床试验注册中心（ChiCTR1800018059）.
Keywords: CD19 Chimeric antigen receptor T cell; Efficacy; Non-Hodgkin's lymphoma; Relapse/refractory; Side effects.