Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells

Salman, Huda; Pinz, Kevin G.; Wada, Masayuki; Shuai, Xiao; Yan, Lulu E.; Petrov, Jessica C.; Ma, Yupo

doi:10.7150/jca.28952

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International Journal of Medical Sciences

Theranostics

Journal of Genomics

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J Cancer 2019; 10(18):4408-4419. doi:10.7150/jca.28952 This issue Cite

Research Paper

Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells

Huda Salman^1✉*, Kevin G. Pinz^2*, Masayuki Wada², Xiao Shuai³, Lulu E. Yan², Jessica C. Petrov¹, Yupo Ma^1,2

1. Department of Internal Medicine, Stony Brook Medicine, Stony Brook University Medical Center, Stony Brook, NY 11794, USA
2. iCell Gene Therapeutics LLC, Research & Development Division, Long Island High Technology Incubator, Stony Brook, NY 11790, USA
3. Department of Hematology, West China hospital of Sichuan University, Chengdu, P.R. China
* These authors contributed equally to this manuscript

Citation:

Salman H, Pinz KG, Wada M, Shuai X, Yan LE, Petrov JC, Ma Y. Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. J Cancer 2019; 10(18):4408-4419. doi:10.7150/jca.28952. https://www.jcancer.org/v10p4408.htm

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Abstract

Acute myeloid leukemia (AML) is an aggressive malignancy lacking targeted therapy due to shared molecular and transcriptional circuits as well as phenotypic markers with normal hematopoietic stem cells (HSCs). Identifying leukemia specific markers expressed on AML or AML subtypes for therapeutic targeting is of exquisite clinical value. Here we show that CD4, a T lymphocytes membrane glycoprotein that interacts with major histocompatibility complex class II antigens and is also expressed in certain AML subsets but not on HSCs is a proper target for genetically engineered chimeric antigen receptor T cells (CAR-T cells). Treatment with CD4 redirected CAR-T cell (CD4CAR) specifically eliminated CD4-expressing AML cell lines in vitro and exhibited a potent anti-leukemic effect in a systemic AML murine model in vivo. We also utilized natural killers as another vehicle for CAR engineered cells and this strategy similarly and robustly eliminated CD4- expressing AML cells in vitro and had a potent in vivo anti-leukemic effect and was noted to have shorter in vivo persistence. Our data offer a proof of concept for immunotherapeutic targeting of CD4 as a strategy to treat CD4 expressing refractory AML as a bridge to stem cell transplant (SCT) in a first in human clinical trial.

Keywords: NK cells, immunotherapy, T-cell malignancies, chimeric antigen receptors, AML

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APA

Salman, H., Pinz, K.G., Wada, M., Shuai, X., Yan, L.E., Petrov, J.C., Ma, Y. (2019). Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. Journal of Cancer, 10(18), 4408-4419. https://doi.org/10.7150/jca.28952.

ACS

Salman, H.; Pinz, K.G.; Wada, M.; Shuai, X.; Yan, L.E.; Petrov, J.C.; Ma, Y. Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. J. Cancer 2019, 10 (18), 4408-4419. DOI: 10.7150/jca.28952.

NLM

CSE

Salman H, Pinz KG, Wada M, Shuai X, Yan LE, Petrov JC, Ma Y. 2019. Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. J Cancer. 10(18):4408-4419.

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