Targeting CD33 in Chemoresistant AML Patient-Derived Xenografts by CAR-CIK Cells Modified with an Improved SB Transposon System.
Animals
Cell Engineering
/ methods
Cell Transplantation
/ methods
Cytokine-Induced Killer Cells
/ immunology
Drug Resistance, Neoplasm
Feasibility Studies
Gene Transfer Techniques
Genetic Therapy
/ methods
Heterografts
Humans
Immunotherapy, Adoptive
/ methods
Leukemia, Experimental
/ therapy
Leukemia, Myeloid, Acute
/ therapy
Mice
Mice, Inbred NOD
Mice, SCID
Receptors, Chimeric Antigen
/ genetics
Sialic Acid Binding Ig-like Lectin 3
/ genetics
THP-1 Cells
Transposases
/ genetics
Treatment Outcome
Xenograft Model Antitumor Assays
AML
CAR
CD33
Sleeping Beauty transposon
cytokine-induced killer cells
immunotherapy
non-viral gene transfer
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
02 09 2020
02 09 2020
Historique:
received:
14
10
2019
revised:
31
03
2020
accepted:
26
05
2020
pubmed:
12
6
2020
medline:
28
8
2021
entrez:
12
6
2020
Statut:
ppublish
Résumé
The successful implementation of chimeric antigen receptor (CAR)-T cell therapy in the clinical context of B cell malignancies has paved the way for further development in the more critical setting of acute myeloid leukemia (AML). Among the potentially targetable AML antigens, CD33 is insofar one of the main validated molecules. Here, we describe the feasibility of engineering cytokine-induced killer (CIK) cells with a CD33.CAR by using the latest optimized version of the non-viral Sleeping Beauty (SB) transposon system "SB100X-pT4." This offers the advantage of improving CAR expression on CIK cells, while reducing the amount of DNA transposase as compared to the previously employed "SB11-pT" version. SB-modified CD33.CAR-CIK cells exhibited significant antileukemic activity in vitro and in vivo in patient-derived AML xenograft models, reducing AML development when administered as an "early treatment" and delaying AML progression in mice with established disease. Notably, by exploiting an already optimized xenograft chemotherapy model that mimics human induction therapy in mice, we demonstrated for the first time that CD33.CAR-CIK cells are also effective toward chemotherapy resistant/residual AML cells, further supporting its future clinical development and implementation within the current standard regimens.
Identifiants
pubmed: 32526203
pii: S1525-0016(20)30285-9
doi: 10.1016/j.ymthe.2020.05.021
pmc: PMC7474266
pii:
doi:
Substances chimiques
CD33 protein, human
0
Receptors, Chimeric Antigen
0
Sialic Acid Binding Ig-like Lectin 3
0
Transposases
EC 2.7.7.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1974-1986Informations de copyright
Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.
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