Compound CAR T-cells as a double-pronged approach for treating acute myeloid leukemia

Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression a...

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Bibliographic Details
Published in:Leukemia 2018-06, Vol.32 (6), p.1317-1326
Main Authors: Petrov, Jessica C., Wada, Masayuki, Pinz, Kevin G., Yan, Lulu E., Chen, Kevin H., Shuai, Xiao, Liu, Hua, Chen, Xi, Leung, Lai-Han, Salman, Huda, Hagag, Nabil, Liu, Fang, Jiang, Xun, Ma, Yupo
Format: Article
Language:English
Subjects:
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Acute myeloid leukemia
Animal models
Anticancer properties
Antigens
Antitumor agents
Biocompatibility
Cancer Research
CD123 antigen
Critical Care Medicine
Cytotoxicity
Hematology
Intensive
Internal Medicine
Leukemia
Lymphocytes T
Medicine
Medicine & Public Health
Monoclonal antibodies
Myeloid leukemia
Oncology
Stem cell transplantation
Stem cells
Therapy
Toxicity
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Summary:Acute myeloid leukemia (AML) bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse. Here, we report on the robust anti-tumor activity of a compound CAR (cCAR) T-cell possessing discrete scFv domains targeting two different AML antigens, CD123, and CD33, simultaneously. We determined that the resulting cCAR T-cells possessed consistent, potent, and directed cytotoxicity against each target antigen population. Using four leukemia mouse models, we found superior in vivo survival after cCAR treatment. We also designed an alemtuzumab safety-switch that allowed for rapid cCAR therapy termination in vivo. These findings indicate that targeting both CD123 and CD33 on AML cells may be an effective strategy for eliminating both AML bulk disease and LSCs, and potentially prevent relapse due to antigen escape or LSC persistence.
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-018-0075-3