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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2020, Vol. 14 Issue (6) : 701-710    https://doi.org/10.1007/s11684-020-0763-z
REVIEW
Chimeric antigen receptor T cell therapies for acute myeloid leukemia
Bin Gu, Jianhong Chu, Depei Wu()
Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Collaborative Innovation Center of Hematology of Soochow University, Suzhou Institute of Blood and Marrow Transplantation, Suzhou 215006, China
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Abstract

Chimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.

Keywords acute myeloid leukemia      CAR T      immunotherapy     
Corresponding Author(s): Depei Wu   
Just Accepted Date: 29 September 2020   Online First Date: 11 January 2021    Issue Date: 24 December 2020
 Cite this article:   
Bin Gu,Jianhong Chu,Depei Wu. Chimeric antigen receptor T cell therapies for acute myeloid leukemia[J]. Front. Med., 2020, 14(6): 701-710.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-020-0763-z
https://academic.hep.com.cn/fmd/EN/Y2020/V14/I6/701
Fig.1  Endogenous T cell receptor (TCR) is comprised of paired a and b chains associated with d, ε, and g chains, and z chains. The antigen is presented by either major histocompatibility complex (MHC) class I or MHC class II. The specificity signal delivered by the TCR is commonly defined as signal 1, which is the recognition signal. T cell activation also requires a co-stimulatory signal, referred to as signal 2. Activating co-stimulatory receptors include CD28, 4-1BB, and others.
Fig.2  Basic structures of chimeric antigen receptors. Chimeric antigen receptors (CARs) recognize cell-surface antigens in a major histocompatibility complex-independent manner and are composed of an extracellular binding domain, a hinge, a transmembrane domain, and intracellular signal domains. The first-generation CAR has a single T cell receptor signal domain comprising a CD3z chain. The second-generation CARs incorporating CD28/4-1BB as a co-stimulatory domain are developed. CARs incorporating three or more signal domains, the so-called third- and fourth-generation CARs, have also been developed and have started to be tested in clinical trials.
Fig.3  (A) Dual-targeting CARs express two different antigen-specific CARs. (B) Bispecific CARs combine two linked scFV within one CAR construct. (C) Suicide CARs were designed to contain the suicide gene to serve as control mechanisms for toxicity management. One example is the inducible caspase 9 (iCasp9). When the small molecule AP1903 is administered, iCasp9 domains dimerize and activate apoptosis independent of CAR activation.
Antigen target Trail number Trail phase Disease First posted Recruitment status Country Sponsor
CD33 NCT03126864 I RR-AML April 24, 2017 Recruiting USA M.D. Anderson Cancer Center
CD33 NCT02799680 I RR-AML June 15, 2016 Unknown China The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
CD33 NCT01864902 I/II RR-AML May 30, 2013 Unknown China Chinese PLA General Hospital
CD33, CD38, CD56, CD117, CD123, CD34, and Muc1 NCT03291444 I RR-AML and MDS September 25, 2017 Recruiting China Zhujiang Hospital
CD33, CD38, CD56, CD123, CD117, CD133, CD34 or Mucl NCT03473457 Not applicable RR-AML March 22, 2018 Recruiting China Zhujiang Hospital
CD33, CD38, CD123, CD56, Muc1, and CLL1 NCT03222674 I/II AML July 19, 2017 Recruiting China Shenzhen Geno-Immune Medical Institute
CD123 NCT03585517 I AML July 13, 2018 Recruiting China Beijing Immunochina Medical Science & Technology Co., Ltd.
CD123 NCT03114670 I Relapse AML after Allo-HSCT April 14, 2017 Recruiting China Affiliated Hospital to Academy of Military Medical Sciences
CD123 NCT03556982 I RR-AML June 14, 2018 Recruiting China The Affiliated Hospital of the Chinese Academy of Military Medical Sciences
CD123 NCT02159495 I RR-AML and persistent/recurrent blastic plasmacytoid dendritic cell neoplasm June 10, 2014 Recruiting USA City of Hope Medical Center
CD123 NCT03672851 I RR-AML September 17, 2018 Enrolling by invitation China Second Affiliated Hospital of Xi’an Jiaotong University
CD123 NCT03766126 I RR-AML December 5, 2018 Recruiting USA University of Pennsylvania
CD123 NCT03190278 I RR-AML June 16, 2017 Recruiting USA Cellectis S.A.
CD123/CLL1 NCT03631576 II/III RR-AML August 15, 2018 Recruiting China Fujian Medical University
CD123 NCT03796390 I AML January 8, 2019 Recruiting China Hebei Senlang Biotechnology Inc., Ltd.
CD123 NCT02937103 I Myeloid malignancies October 18, 2016 Recruiting China Southwest Hospital, China
CD123 NCT02623582 I AML December 7, 2015 Terminated USA University of Pennsylvania
NKG2D NCT02203825 I AML, MM July 30, 2014 Completed USA Celyad
NKG2D NCT03018405 I/II AML, MM January 12, 2017 Recruiting USA Celyad
Lewis Y NCT01716364 I AML October 29, 2012 Active, not recruiting Australia Peter MacCallum Cancer Centre
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