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浙江大学学报(医学版)  2022, Vol. 51 Issue (2): 167-174    DOI: 10.3724/zdxbyxb-2022-0049
专题报道     
嵌合抗原受体T细胞治疗复发/难治B细胞非霍奇金淋巴瘤患者的长期疗效
付珊1,2,3,4,胡永仙1,2,3,4,*(),黄河1,2,3,4,*()
1.浙江大学医学院附属第一医院骨髓移植中心,浙江 杭州 310003
2.浙江大学医学中心良渚实验室,浙江 杭州 311121
3.浙江大学血液学研究所,浙江 杭州 310058
4.浙江省干细胞与细胞免疫治疗工程实验室,浙江 杭州 310058
Long-term efficacy of CAR-T cell therapy for patients with relapsed/refractory B cell non-Hodgkin lymphoma
FU Shan1,2,3,4,HU Yongxian1,2,3,4,*(),HUANG He1,2,3,4,*()
1. Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;
2. Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou 311121, China;
3. Institute of Hematology, Zhejiang University, Hangzhou 310058, China;
4. Zhejiang Provincial Laboratory for Stem Cell and Immune Therapy, Hangzhou 310058, China
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摘要:

目的:评价嵌合抗原受体(CAR)T细胞治疗复发/难治B细胞非霍奇金淋巴瘤(B-NHL)的长期疗效。方法:收集2016年6月至2020年6月在浙江大学医学院附属第一医院骨髓移植中心应用CAR-T细胞治疗的27例复发/难治B-NHL患者的资料,随访日期截至2022年2月1日。运用Kaplan-Meier生存分析评估患者总存活率和无进展存活率,并统计相关不良反应。结果:27例患者中位随访时间为32(1,56)个月,CAR-T细胞治疗总反应率为85.2%(23/27),完全缓解率为63.0%(17/27),部分缓解率为22.2%(6/27)。患者3年总存活率为(50.0±10.1)%,无进展存活率为(44.4±9.6)%。CAR-T细胞治疗后获完全缓解患者的总存活率和无进展存活率均优于未获完全缓解患者[总存活率分别为(66.9±12.7)%和(20.0±12.6)%,P=0.01;无进展存活率分别为(64.7±11.6)%和(10.0±9.5)%,P<0.01]。CD19单靶点和CD19/CD22双靶点的CAR-T细胞治疗患者总存活率和无进展存活率差异无统计学意义(均P>0.05)。92.6%(25/27)的患者发生细胞因子释放综合征;88.9%(24/27)的患者治疗期间发生Ⅲ~Ⅳ级骨髓抑制;其他不良反应包括免疫效应细胞相关神经毒性综合征、乙型肝炎病毒激活以及肺部或胃肠道感染等。未观察到远期不良反应发生。结论:CAR-T细胞治疗是复发/难治B-NHL患者的有效治疗方案,不良反应可控。CAR-T细胞治疗后获得完全缓解及随访至1年时处于存活状态的患者可能有更好的长期存活率。

关键词: B细胞非霍奇金淋巴瘤嵌合抗原受体T细胞复发/难治长期疗效    
Abstract:

Objective: To evaluate the long-term efficacy of chimeric antigen receptor (CAR) T cell therapy in treatment of relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL). Methods: Clinical data of 27 patients with relapsed/refractory B-NHL treated with CAR-T cell in Bone Marrow Transplantation Center, the First Affiliated Hospital of Zhejiang University School of Medicine from June 2016 to June 2020 were analyzed. Patients were followed up to February 1, 2022. The overall survival rate, progression free survival (PFS) rate were evaluated by Kaplan-Meier analysis, and the adverse reactions were recorded. Results: The median follow-up time of 27 patients was 32? (1, 56) months. The total response rate was 85.2% (23/27), the complete response rate was 63.0% (17/27), and the partial response rate was 22.2% (6/27). The 3-year overall survival rate was (50.0±10.1)%, and the PFS rate was (44.4±9.6)%. After CAR-T cell therapy, the overall survival and PFS of patients in the complete response group were significantly better than those in the non-complete response group [overall survival rate: (66.9±12.7)% vs. (20.0±12.6)%, P=0.01; PFS rate: (64.7±11.6)% vs. (10.0±9.5)%, P<0.01]. There was no significant difference in overall survival rate and PFS rate between CD19 targeted and CD19/CD22 dual-targeted CAR-T cell therapy (bothP>0.05). Cytokine release syndrome developed in 92.6% (25/27) of patients, and 88.9% (24/27) of patients had grade Ⅲ–Ⅳ myelosuppression. Other adverse reactions include immune effector cell-associated neurotoxicity syndrome, hepatitis B virus activation, and lung or gastrointestinal infections. No long-term adverse reactions occurred.Conclusions: CAR-T cell therapy is effective for patients with relapsed/refractory B-NHL, and the adverse reactions are controllable. The patients who obtain complete response after CAR-T cell therapy or survive for one year after therapy may have better long-term survival.

Key words: B-cell non-Hodgkin lymphoma    Chimeric antigen receptor T cell    Relapsed/refractory    Long-term efficacy
收稿日期: 2022-02-15 出版日期: 2022-08-02
CLC:  R73  
基金资助: 国家自然科学基金(81730008,81870153)
通讯作者: 胡永仙,黄河     E-mail: 1313016@zju.edu.cn
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引用本文:

付珊,胡永仙,黄河. 嵌合抗原受体T细胞治疗复发/难治B细胞非霍奇金淋巴瘤患者的长期疗效[J]. 浙江大学学报(医学版), 2022, 51(2): 167-174.

FU Shan,HU Yongxian,HUANG He. Long-term efficacy of CAR-T cell therapy for patients with relapsed/refractory B cell non-Hodgkin lymphoma. J Zhejiang Univ (Med Sci), 2022, 51(2): 167-174.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0049        https://www.zjujournals.com/med/CN/Y2022/V51/I2/167

图 1  CAR-T细胞治疗B细胞非霍奇金淋巴瘤患者的总存活率和无进展存活率A、B:所有患者的总存活率和无进展存活率;C、D:完全缓解组和未获完全缓解组患者的总存活率和无进展存活率;E、F:CD19单靶点和CD19/CD22双靶点的CAR-T细胞治疗患者的总存活率和无进展存活率.

例序

性别

年龄(岁)

病理分型

Lugano分期

治疗前疾病状态

治疗前化疗线数

靶点

CAR-T细胞输注剂量(106/kg)

最佳治疗反应

CAR-T细胞基因转染率(%)

CRS等级

ICANS

Ⅲ~Ⅳ级骨髓抑制

转归

1

39

DLBCL,非GCB

Ⅲ期A组

复发

2

CD19/CD22

6.4

完全缓解

22.0

1

存活

2

23

DLBCL,非GCB

Ⅳ期A组

复发

4

CD19/CD22

4.9

部分缓解

38.0

3

死亡

3

62

DLBCL,非GCB

Ⅳ期B组

复发

4

CD19/CD22

6.7

部分缓解

65.0

2

存活

4

62

DLBCL,非GCB

Ⅲ期A组

难治

1

CD19/CD22

9.4

完全缓解

44.0

3

存活

5

55

伯基特淋巴瘤

Ⅳ期B组

复发

2

CD19/CD22

5.5

部分缓解

46.0

2

死亡

6

32

B-LBL

Ⅲ期A组

复发

3

CD19/CD22

6.3

完全缓解

57.0

2

死亡

7

29

滤泡性淋巴瘤

Ⅳ期B组

难治

3

CD19/CD22

6.9

完全缓解

52.0

1

存活

8

68

DLBCL,GCB

Ⅳ期A组

复发

2

CD19/CD22

7.8

部分缓解

65.0

2

存活

9

58

DLBCL,GCB

Ⅲ期A组

复发

3

CD19/CD22

5.0

完全缓解

57.0

2

存活

10

43

DLBCL,非GCB

Ⅲ期B组

复发

2

CD19/CD22

5.7

完全缓解

34.0

1

存活

11

66

DLBCL,非GCB

Ⅳ期A组

复发

3

CD19/CD22

6.5

部分缓解

70.0

2

死亡

12

64

DLBCL,非GCB

Ⅳ期B组

复发

2

CD19/CD22

5.6

完全缓解

49.0

2

存活

13

49

DLBCL,非GCB

Ⅲ期A组

难治

2

CD19/CD22

5.0

完全缓解

30.0

0

存活

14

25

DLBCL,非GCB

Ⅳ期B组

难治

1

CD19/CD22

9.0

完全缓解

55.0

2

死亡

15

66

DLBCL,非GCB

Ⅲ期A组

复发

2

CD19/CD22

8.0

完全缓解

45.0

2

存活

16

50

B-LBL

Ⅳ期B组

复发

4

CD19/CD22

5.4

部分缓解

48.0

1

死亡

17

35

DLBCL,GCB

Ⅳ期A组

复发

5

CD19

10.0

完全缓解

34.0

2

死亡

18

27

DLBCL,非GCB

Ⅳ期B组

难治

2

CD19

2.4

完全缓解

25.0

2

死亡

19

35

DLBCL,非GCB

Ⅲ期A组

难治

2

CD19

1.6

疾病进展

35.0

3

死亡

20

43

DLBCL,GCB

Ⅳ期B组

难治

2

CD19

4.5

疾病进展

43.0

3

死亡

21

43

DLBCL,非GCB

Ⅲ期A组

复发

3

CD19

8.0

完全缓解

54.0

1

存活

22

47

CLL/SLL

Ⅳ期A组

复发

3

CD19

2.3

疾病进展

50.0

2

死亡

23

60

DLBCL,非GCB

Ⅲ期B组

难治

2

CD19

5.0

完全缓解

42.0

2

死亡

24

50

DLBCL,GCB

Ⅱ期A组

复发

2

CD19

6.3

完全缓解

39.0

3

存活

25

33

DLBCL

Ⅳ期A组

复发

3

CD19

1.6

疾病进展

23.0

1

死亡

26

62

DLBCL,非GCB

Ⅳ期B组

复发

2

CD19

3.5

完全缓解

56.0

0

存活

27

71

DLBCL,非GCB

Ⅲ期A组

复发

1

CD19

5.4

完全缓解

59.0

2

存活

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doi: 10.1038/nature22395
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doi: 10.1126/science.aar6711
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doi: 10.1056/NEJMoa1707447
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doi: 10.1200/JCO.2013.54.8800
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doi: 10.1016/j.bbmt.2018.12.758
11 WEIG, ZHANGY, ZHAOH, et al.CD19/CD22 dual-targeted CAR T-cell therapy for relapsed/refractory aggressive B-cell lymphoma: a safety and efficacy study[J]Cancer Immunol Res, 2021, 9( 9): 1061-1070.
doi: 10.1158/2326-6066.CIR-20-0675
12 ZENGW, ZHANGQ, ZHUY, et al.Engineering novel CD19/CD22 dual-target CAR-T cells for improved anti-tumor activity[J]Cancer Invest, 2022, 40( 3): 282-292.
doi: 10.1080/07357907.2021.2005798
13 SHAHN N, FRYT J. Mechanisms of resistance to CAR T cell therapy[J]Nat Rev Clin Oncol, 2019, 16( 6): 372.
doi: 10.1038/s41571-019-0184-6
14 NIEY, LUW, CHEND, et al.Mechanisms underlying CD19-positive ALL relapse after anti-CD19 CAR T cell therapy and associated strategies[J]Biomark Res, 2020, 8( 1): 18.
doi: 10.1186/s40364-020-00197-1
15 黄 河, 黄 玥, 胡永仙, 等. 嵌合抗原受体T细胞治疗后急性淋巴细胞白血病复发的研究进展[J]. 浙江医学, 2020, 42(23): 2487-2494
HUANG He, HUANG Yue, HU Yongxian, et al. Recent advance on relapse of acute lymphoblastic leukemia treated with CAR T cell therapy[J]. Zhejiang Medical Journal, 2020, 42(23): 2487-2494. (in Chinese)
16 GHAFOURIS, TIMMERMANJ, LARSONS, et al.Axicabtagene ciloleucel CAR T-cell therapy for relapsed/refractory secondary CNS non-Hodgkin lymphoma: comparable outcomes and toxicities, but shorter remissions may warrant alternative consolidative strategies?[J]Bone Marrow Transplant, 2021, 56( 4): 974-977.
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