ABSTRACT
Chimeric antigen receptor (CAR)-based immunotherapy has achieved dramatic success in the treatment of B cell malignancies, based on the summary of current research data, and has shown good potential in early phase cancer clinical trials. Modified constructs are being optimized to recognize and destroy tumor cells more effectively. By targeting the proper B-lineage-specific antigens such as CD19 and CD20, adoptive immunotherapy has demonstrated promising clinical results and already plays a role in the treatment of several lymphoid malignancies, which highlights the importance of target selection for other CAR therapies. The high efficacy of CAR-T cells has resulted in the approval of anti-CD19-directed CAR-T cells for the treatment of B cell malignancies. In this review, we focus on the basic structure and current clinical application of CAR-T cells, detail the research progress of CAR-T for different antigenic targets in hematological malignancies, and further discuss the current barriers and proposed solutions, investigating the possible mechanisms of recurrence of CAR-T cell therapy. A summary of the paper is also given to overview as the prospects for this therapy.
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Abbreviations
- 1G:
-
First generation
- 2G:
-
Second generation
- 3G:
-
Third generation
- 4G:
-
Fourth generation
- AICD:
-
Activation-induced cell death
- ALCL:
-
Anaplastic large cell lymphoma
- ALL:
-
Acute lymphoblastic leukemia
- AML:
-
Acute myelocytic leukemia
- ASH:
-
American Society of Hematology
- ASTCT:
-
American Society for Transplantation and Cellular Therapy
- axi-cel:
-
Axicabtagene ciloleucel
- BBB:
-
Blood-brain barrier
- Bcl-2:
-
B cell lymphoma-2
- BCMA:
-
B cell maturation agent
- BCP ALL:
-
Pre-B cell ALL
- CAR:
-
Chimeric antigen receptor
- cCAR:
-
Compound CAR
- CD7KO:
-
CD7 knockout
- CHO:
-
Chinese hamster ovary
- CLL:
-
Chronic lymphocytic leukemia
- CNS:
-
Central nervous system
- CR:
-
Complete remission
- CRP:
-
C-reactive protein
- CRS:
-
Cytokine release syndrome
- DFS:
-
Disease-free survival
- DL:
-
Dose levels
- DLBCL:
-
Diffuse large B cell lymphoma
- DLT:
-
Dose-limiting toxicity
- DOR:
-
Duration of response
- EFS:
-
Event-free survival
- FDA:
-
Food and Drug Administration
- FHCRC:
-
Fred Hutchinson Cancer Research Center
- FL:
-
Follicular lymphoma
- FLT3:
-
FMS-like tyrosine kinase 3
- GMP:
-
Good manufacturing practice
- IL-3R:
-
IL-3 receptor
- HCL:
-
Hairy cell leukemia
- HL:
-
Hodgkin lymphoma
- HSCT:
-
Hematopoietic stem cell transplantation
- HSPCs:
-
Hematopoietic stem and progenitor cells
- ICANS:
-
Immune effector cell-associated neurotoxicity syndrome
- ITD:
-
Internal tandem duplication
- LSCs:
-
Leukemic stem cells
- mAb:
-
Monoclonal antibody
- mAbs:
-
Monoclonal antibodies
- MCL:
-
Mantle cell lymphoma
- MM:
-
Multiple myeloma
- MRD:
-
Minimal residual disease
- MSKCC:
-
Memorial Sloan Kettering Cancer Center
- MZL:
-
Marginal-zone lymphomas
- NCI:
-
National Cancer Institute
- NHL:
-
Non-Hodgkin lymphoma
- NK:
-
Natural killer
- OR:
-
Objective response
- ORR:
-
Overall response rate
- ORS:
-
Overall rate of survival
- OS:
-
Overall survival
- PBMCs:
-
Peripheral blood mononuclear cells
- PEBL:
-
Protein expression blocker
- PFS:
-
Progression-free survival
- PMBCL:
-
Primary mediastinal B cell lymphoma
- PR:
-
Partial remission
- RFS:
-
Relapse-free survival
- R/R:
-
Relapsed or refractory
- RT:
-
Richter transformation
- scFV:
-
Single-chain fragment variable
- sCRS:
-
Severe cytokine release syndrome
- T-ALL:
-
T cell acute lymphoblastic leukemia
- TCR:
-
T cell receptor
- Tcm:
-
Central memory T
- TFL:
-
Transformed lymphoma
- TMs:
-
Target modules
- TKD:
-
Tyrosine kinase domain
- TSA:
-
Tumor-associated antigen
- Tscm:
-
Memory T stem cells
- U Penn:
-
University of Pennsylvania
- VGPR:
-
Very good partial remission
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This work was supported by the Science and Technology Program of Guangzhou, China (grant number 201704020216); the Natural Science Foundation of Guangdong Province, China (grant number 2018B030311042); and the Frontier Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory, China (grant number 2018GZR110105014).
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YHL and MRW participated in the design of the study. JJZ, ZFL, SS, and YW equally contributed to searching literatures and drafting the manuscript. LTZ partially contributed to searching literatures. YHL, MRW, and LTZ revised and polished the manuscript. All authors read and approved the final manuscript.
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Zhao, J., Wu, M., Li, Z. et al. Chimeric antigen receptor therapy in hematological malignancies: antigenic targets and their clinical research progress. Ann Hematol 99, 1681–1699 (2020). https://doi.org/10.1007/s00277-020-04020-7
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DOI: https://doi.org/10.1007/s00277-020-04020-7