CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

doi:10.1007/s11684-021-0904-z

Front. Med.

2021, Vol. 15

Issue (6) : 783-804 https://doi.org/10.1007/s11684-021-0904-z

REVIEW

CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

Jianqing Mi¹, Jie Xu^1,², Jianfeng Zhou³, Weili Zhao¹, Zhu Chen¹, J. Joseph Melenhorst²(

), Saijuan Chen¹(

)

¹. State Key Laboratory of Medical Genomics, Shanghai Institute of Haematology, National Research Centre for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
². Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
³. Immunotherapy Research Centre for Hematologic Diseases of Hubei Province, Department of Haematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

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Abstract

The current standard of care in hematological malignancies has brought considerable clinical benefits to patients. However, important bottlenecks still limit optimal achievements following a current medical practice. The genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological disorders. Consequently, new treatment strategies are necessary to improve clinical outcomes. Chimeric antigen receptor T-cell (CAR T) immunotherapy opens a new path for targeted therapy of hematological malignancies. In this review, through a representative case study, we summarize the current experience of CAR T-cell therapy, the management of common side effects, the causative mechanisms of therapy resistance, and new strategies to improve the efficacy of CAR T-cell therapy.

Keywords CAR T cells hematological malignancies review

Corresponding Author(s): J. Joseph Melenhorst,Saijuan Chen

Just Accepted Date: 29 November 2021 Online First Date: 13 December 2021 Issue Date: 27 December 2021

Cite this article:

Jianqing Mi,Jie Xu,Jianfeng Zhou, et al. CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies[J]. Front. Med., 2021, 15(6): 783-804.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0904-z
https://academic.hep.com.cn/fmd/EN/Y2021/V15/I6/783

Tab.1 Major clinical trials of CAR T-cell therapy for relapsed/refractory B-ALL and CLL

Tab.2 Outstanding clinical trials of anti-CD19 CAR T-cell therapy for B cell NHL

Tab.3 Clinical trials of anti-BCMA CAR T-cell therapy for MM

Fig.1 Graphic illustrations depict the underlying mechanisms of CAR T-cell therapy resistance. From the immune effector perspective, T-cell quality is a key determinant of CAR T-cell cytotoxicity. A number of cases failed in receiving infusion or favorable outcome because of impaired T lymphocyte, which is attributable to T-cell exhaustion or CAR immunogenicity. In tumor setting, the interplay of cellular and non-cellular substances in tumor microenvironment is considered as a barrier in solid tumor CAR T-cell treatment. The variability of tumor antigen expression in cancer cell equally causes difficulties in CAR T-cell recognition and targeting.

Fig.2 Structural improvements in newly developed CARs. These innovations aim to guide CAR to target to different tumor antigens simultaneously or successively, thereby getting over the obstacles of antigen escape and targeting failure.

Study site	Disease	Targets	Construct of CAR	No. of cases infused	Dose	Best response (CR)	Relapse	Median follow-up (month)	Severe CRS	Severe neurotoxicity	Reference and registered number
Department of Molecular Biology and Immunology, Chinese PLA General Hospital	B-ALL	CD19/CD22	Tandem construct	6	(1.7–3) × 10⁶/kg	6/6	6/6	NA	0	0	[133]
	B-ALL	CD19/CD22	Tandem construct	6	(1.7–3) × 10⁶/kg	6/6	1 CD19^neg/CD22^dim	NA	0	0	NCT03185494
Beijing Boren Hospital	ALL	CD19/CD22	Separate constructs by sequential infusions	20	CD19-CAR T: (3.3–42.8) × 10⁵/kg	20/20	15%	18	5%	5%	[136]
Beijing Boren Hospital	ALL	CD19/CD22	Separate constructs by sequential infusions	20	CD22-CAR T: (0.25–47.4)×10⁵/kg	20/20	3/20 (2 CD19 neg, 1 CD22 dim)	18	1/20	1/20	ChiCTR-OIB-17013670
Tongji Hospital, Huazhong University of Science and Technology	B-ALL	CD19/CD22	Separate constructs by sequential infusions	B-ALL 51	CD19-CAR T: (2.6±1.5) × 10⁶/kg in B-ALL; (5.1±2.1)×10⁶/kg in NHL	ALL CR: 48/50	ALL 24 relapsed (23 CD19⁺CD22^+?relapsed, 1 CD19^–/CD22^dim relapsed)	16.7	22.4%	1.12%	[134]
	NHL	CD19/CD22	Separate constructs by sequential infusions	NHL 38	CD22-CAR T: (2.7±1.2)×10⁶/kg in B-ALL; (5.3±2.4)×10⁶/kg in NHL	NHL CR: 18/36	NHL NA	14.4	22.4%	1.12%	ChiCTR-OPN-16008526
Bone Marrow Transplantation Department Great Ormond Street Hospital	B-ALL	CD19/CD22	Bicistronic construct	10	Dose 1: 3x10⁶/kg?	7/10	3/10	8	0	0	[137]
	B-ALL	CD19/CD22	Bicistronic construct	10	Dose 2: 5x10⁶/kg	7/10	1 CD19^neg/CD22^dim	8	0	0	NCT03289455
Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee	NHL	CD19/CD20	Tandem construct	22	2.5x10⁶/kg	14/22	NA	NA	0	0	[138]
	NHL	CD19/CD20	Tandem construct	22	2.5x10⁶/kg	14/22	NA	NA	0	0	NCT03019055
Department of Molecular Biology and Immunology Chinese PLA General Hospital	NHL	CD19/CD20	Tandem construct	31	(0.5–8)×10⁶/kg	20/28	4 relapsed 1 with antigen loss	19.1	4/28	0	[139]
	NHL	CD19/CD20	Tandem construct	31	(0.5–8)×10⁶/kg	20/28	4 relapsed 1 with antigen loss	19.1	4/28	0	NCT03097770
Department of Hematology, the Affiliated Hospital of Xuzhou Medical University	MM	CD19/BCMA	Separate constructs by simultaneous infusions	21	CD19‐CAR T (1×10⁶ cells /kg)	9 sCR, 3 CR/21	1/21	5.97	1/21	0	[135]
	MM	CD19/BCMA	Separate constructs by simultaneous infusions	21	BCMA‐CAR T (1×10⁶cells/kg)	9 sCR, 3 CR/21	1/21	5.97	1/21	0	ChiCTR-OIC-17011272
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology	MM	BCMA/CD38	Tandem construct	16	0.5, 1.0, 2.0, 3.0 and 4.0×10⁶ cells/kg	8 sCR/16	NA	NA	0	0	[140]
	MM	BCMA/CD38	Tandem construct	16	0.5, 1.0, 2.0, 3.0 and 4.0×10⁶ cells/kg	8 sCR/16	NA	NA	0	0	ChiCTR1800018143

Tab.4 Major clinical trials of dual-targeting CAR T in hematological B-cell malignancies

Fig.3 Current strategies of improving CAR T-cell practical application. From CAR construct optimization to clinical management on adverse events, CAR T-cell immunotherapy is rapidly being advanced to make it more available and accessible to lymphoid hematological malignancies. CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; HLH, hemophagocytic lymphohisticytosis; TLS, tumor lysis syndrome.

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