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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2022, Vol. 16 Issue (2) : 285-294    https://doi.org/10.1007/s11684-021-0843-8
RESEARCH ARTICLE
Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse large B-cell lymphoma in Chinese patients
Lei Fan, Li Wang, Lei Cao, Huayuan Zhu, Wei Xu(), Jianyong Li()
Department of Hematology, Pukou CLL Center, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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Abstract

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has shown impressive efficacy in treating B-cell malignancies. A single-center phase I dose-escalation study was conducted to evaluate the safety and efficacy of T cells transduced with CBM.CD19 CAR, a second-generation anti-CD19 CAR bearing 4-1BB costimulatory molecule, for the treatment of patients with refractory diffuse large B-cell lymphoma (DLBCL). Ten heavily treated patients with refractory DLBCL were given CBM.CD19 CAR-T cell (C-CAR011) treatment. The overall response rate was 20% and 50% at 4 and 12 weeks after the infusion of C-CAR011, respectively, and the disease control rate was 60% at 12 weeks after infusion. Treatment-emergent adverse events occurred in all patients. The incidence of cytokine release syndrome in all grades and grade≥3 was 90% and 0, respectively, which is consistent with the safety profile of axicabtagene ciloleucel and tisagenlecleucel. Neurotoxicity or other dose-limiting toxicities was not observed in any dose cohort of C-CAR011 therapy. Antitumor efficacy was apparent across dose cohorts. Therefore, C-CAR011 is a safe and effective therapeutic option for Chinese patients with refractory DLBCL, and further large-scale clinical trials are warranted.
Keywords CAR-T cell therapy      refractory diffuse large B-cell lymphoma      cytokine release syndrome      dose-limiting toxicity     
Corresponding Author(s): Wei Xu,Jianyong Li   
About author:

Mingsheng Sun and Mingxiao Yang contributed equally to this work.
Just Accepted Date: 09 August 2021   Online First Date: 02 November 2021    Issue Date: 26 April 2022
 Cite this article:   
Lei Fan,Li Wang,Lei Cao, et al. Phase I study of CBM.CD19 chimeric antigen receptor T cell in the treatment of refractory diffuse large B-cell lymphoma in Chinese patients[J]. Front. Med., 2022, 16(2): 285-294.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0843-8
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I2/285
Fig.1  Schematic of study design. D, day; W, week.
Characteristic Low-dose cohort Middle-dose cohort High-dose cohort Total
(N = 3) (N = 3) (N = 4) (N = 12a)
Age (year) 　 　
Mean±SD 50.3±5.8 28.8±3.2 52.9±11.0 44.5±13.2
Range 43.7-53.0 25.4-31.6 45.4-69.2 25.4-69.2
Gender, n (%)
Male 2 (66.7) 3 (100.0) 2 (50.0) 9 (75.0)
Female 1 (33.3) 0 2 (50.0) 3 (25.0)
Height (cm)
Mean±SD 169.0±4.4 174.3±4.9 168.5±6.1 170.5±4.93
Range 164–172 171–180 163–176 163–180
Weight (kg)
Mean±SD 69.7±9 73±7 67.9±12.2 69.6±8.3
Range 64-80 68-81 60-86 60-86
Days to pathological diagnosisb
Mean±SD -440.5±21.9 -415.0±261.6 -331.3±61.8 -386.4±124.6
Range -456 to -425 -600 to -230 -399 to -278 -600 to -230
Modified Ann Arbor stage before enrollment, n (%)
I or II 0 1 (33.3) 1 (25.0) 4 (33.35)
III or IV 3 (100.0) 2 (66.7) 3 (75.0) 8 (66.7)
Symptom A or B, n (%)
A 3 (100.0) 3 (100.0) 1 (25.0) 9 (75.0)
B 0 0 3 (75.0) 3 (25.0)
Number of prior lines of treatment, n (%)
1−2 0 0 0 1 (8.3)c
3 1 (33.3) 1 (33.3) 1 (25.0) 3 (25.0)
>3 2 (66.7) 2 (66.7) 3 (75.0) 8 (66.7)d
Best response to previous regimens, n (%)
CR 0 0 1 (25.0) 1 (8.3)
PR 0 2 (66.7) 0 2 (16.7)
SD 1 (33.3) 1 (33.3) 1 (25.0) 4 (33.3)
PD 2 (66.7) 0 2 (50.0) 5 (41.7)
Tab.1  Baseline demographic and disease characteristics of patients who received C-CAR011 treatment
Factor, n (%) Low-dose cohort Middle-dose cohort High-dose cohort Total
(N = 3) (N = 3) (N = 4) (N = 10)
Patients with≥1 TEAE 3 (100%) 3 (100%) 4 (100%) 10 (100%)
Patients with≥1 TEAE (NCI CTCAE≥3) 3 (100%) 3 (100%) 4 (100%) 10 (100%)
Patients with≥1 Serious TEAE 1 (33.3%) 0 0 1 (10%)
Tab.2  TEAE after treatment (Safety Analysis Set, SAS)
Cohort Patient Symptom description Level Use of tocilizumab Use of corticosteroids Other medication Action to study product Withdrawal
Yes/no Yes/no Yes/no Yes/no
Low-dose cohort S002 Fever/chills/elevated transaminase 1 No No Yes Not applicable No
　 S003 Elevated transaminase 1 No No No Not applicable No
　 S004 Fever/diarrhea 1 No No Yes Continue No
Middle-dose cohort S008 Elevated transaminase 1 No No Yes Not applicable No
　 S010 Diarrhea/constipation 1 No No Yes Continue No
High-dose cohort S014 Fever 1 No No Yes Not applicable No
　 S015 Fever/anorexia/vomiting/hypoxemia /elevated transaminase 2 No No Yes Continue No
　 S016 Fever/elevated transaminase 1 No No Yes Not applicable No
　 S018 Fever/fatigue 1 No No Yes Continue No
Tab.3  Description of cytokine release syndrome
Response Low-dose cohort Middle-dose cohort High-dose cohort Total
(N = 3) (N = 3) (N = 4) (N = 10)
Week 4, n (%) 　 　 　 　
CR 0 0 0 0
PR 1 (33.3%) 0 1 (25.0%) 2 (20.0%)
SD 1 (33.3%) 3 (100.0%) 2 (50.0%) 6 (60.0%)
PD 1 (33.3%) 0 1 (25.0%) 2 (20.0%)
NA 0 0 0 0
ORRa 1 (33.3%) 0 1 (25.0%) 2 (20.0%)
95% CI 0.8%−90.6% 0.0%−70.8% 0.6%−80.6% 2.5%−55.6%
week 12, n (%) 　 　 　 　
CR 2 (66.7%) 0 1 (25.0%) 3 (30.0%)
PR 0 1 (33.3%) 1 (25.0%) 2 (20.0%)
SD 0 1 (33.3%) 0 1 (10.0%)
PD 0 1 (33.3%) 1 (25.0%) 2 (20.0%)
NA 0 0 0 0
ORRa 2 (66.7%) 1 (33.3%) 2 (50.0%) 5 (50.0%)
95% CI 9.4%−99.2%) 0.8%−90.6% 6.8%−93.2% 18.7%−81.3%
DCRb 2 (66.7%) 2 (66.7%) 2 (50.0%) 6 (60.0%)
95% CI 9.4%−99.2% 9.4%−99.2% 6.8%−93.2% 26.2%−87.8%
　
Tab.4  Evaluation of efficacy (Full Analysis Set, FAS)
Fig.2  (A) Persistence of C-CAR011 in peripheral blood (PB); (B) Percentage of CD45+CD19+ cells in PB. d, day; w, week; Pt, patient.
Fig.3  Levels of serum cytokines in peripheral blood at baseline and after C-CAR011 infusions. d, day; w, week; Pt, patient.
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