Chimeric antigen receptor therapy in hematological malignancies: antigenic targets and their clinical research progress

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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Fig. 1

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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Funding

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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Correspondence to Yuhua Li.

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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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Keywords

  • Chimeric antigen receptor
  • Targeted therapy
  • Adoptive cell therapy
  • Hematological malignancies
  • Clinical efficacy
  • Recurrence