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CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells

Immunotherapies, such as chimeric antigen receptor (CAR) modified T cells and antibody-drug conjugates (ADCs), have revolutionized the treatment of cancer, especially of lymphoid malignancies. The application of targeted immunotherapy to patients with acute myeloid leukemia (AML) has been limited in...

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Main Authors: Liu, Yi (Author) , Wang, Sanmei (Author) , Schubert, Maria-Luisa (Author) , Lauk, Annika (Author) , Yao, Hao (Author) , Blank, Maximilian Felix (Author) , Cui, Chunhong (Author) , Janssen, Maike (Author) , Schmidt, Christina (Author) , Göllner, Stefanie (Author) , Kleist, Christian (Author) , Zhou, Fengbiao (Author) , Rahfeld, Jens-Ulrich (Author) , Sauer, Tim (Author) , Schmitt, Michael (Author) , Müller-Tidow, Carsten (Author)
Format: Article (Journal)
Language:English
Published: 2022
In: International journal of cancer
Year: 2022, Volume: 150, Issue: 7, Pages: 1141-1155
ISSN:1097-0215
DOI:10.1002/ijc.33865
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/ijc.33865
Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.33865
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Author Notes:Yi Liu, Sanmei Wang, Maria-Luisa Schubert, Annika Lauk, Hao Yao, Maximilian Felix Blank, Chunhong Cui, Maike Janssen, Christina Schmidt, Stefanie Göllner, Christian Kleist, Fengbiao Zhou, Jens-Ulrich Rahfeld, Tim Sauer, Michael Schmitt, Carsten Müller-Tidow
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Summary:Immunotherapies, such as chimeric antigen receptor (CAR) modified T cells and antibody-drug conjugates (ADCs), have revolutionized the treatment of cancer, especially of lymphoid malignancies. The application of targeted immunotherapy to patients with acute myeloid leukemia (AML) has been limited in particular by the lack of a tumor-specific target antigen. Gemtuzumab ozogamicin (GO), an ADC targeting CD33, is the only approved immunotherapeutic agent in AML. In our study, we introduce a CD33-directed third-generation CAR T-cell product (3G.CAR33-T) for the treatment of patients with AML. 3G.CAR33-T cells could be expanded up to the end-of-culture, that is, 17 days after transduction, and displayed significant cytokine secretion and robust cytotoxic activity when incubated with CD33-positive cells including cell lines, drug-resistant cells, primary blasts as well as normal hematopoietic stem and progenitor cells (HSPCs). When compared to second-generation CAR33-T cells, 3G.CAR33-T cells exhibited higher viability, increased proliferation and stronger cytotoxicity. Also, GO exerted strong antileukemia activity against CD33-positive AML cells. Upon genomic deletion of CD33 in HSPCs, 3G.CAR33-T cells and GO preferentially killed wildtype leukemia cells, while sparing CD33-deficient HSPCs. Our data provide evidence for the applicability of CD33-targeted immunotherapies in AML and its potential implementation in CD33 genome-edited stem cell transplantation approaches.
Item Description:First published: 11 November 2021
Gesehen am 24.04.2023
Physical Description:Online Resource
ISSN:1097-0215
DOI:10.1002/ijc.33865

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