دورية أكاديمية
أعرض في EDS

Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia.

التفاصيل البيبلوغرافية
العنوان: Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia.
المؤلفون: El Khawanky N; Precision Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.; School of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.; Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Faculty of Biology, University of Freiburg, Freiburg, Germany., Hughes A; School of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia., Yu W; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Myburgh R; Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland., Matschulla T; Institute of Experimental and Clinical Pharmacology and Toxicology, Division II, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Taromi S; Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; Faculty of Medical and Life Sciences, University Furtwangen, Villingen-Schwenningen, Germany., Aumann K; Department of Pathology, Institute for Clinical Pathology, University Medical Center Freiburg, Freiburg, Germany., Clarson J; Precision Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.; Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia., Vinnakota JM; Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Shoumariyeh K; Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Miething C; Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Lopez AF; School of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia., Brown MP; School of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.; Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, SA, Australia.; Cancer Clinical Trials Unit, Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, SA, Australia., Duyster J; Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Hein L; Institute of Experimental and Clinical Pharmacology and Toxicology, Division II, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Manz MG; Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland., Hughes TP; Precision Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.; School of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.; Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australia., White DL; Precision Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia.; School of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.; School of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA, Australia., Yong ASM; Precision Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia. agnes.yong@health.wa.gov.au.; School of Medicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia. agnes.yong@health.wa.gov.au.; Department of Haematology, Royal Perth Hospital, Perth, WA, Australia. agnes.yong@health.wa.gov.au.; School of Medicine, The University of Western Australia, Perth, WA, Australia. agnes.yong@health.wa.gov.au., Zeiser R; Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. robert.zeiser@uniklinik-freiburg.de.; Signaling Research Centres BIOSS and CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany. robert.zeiser@uniklinik-freiburg.de.
المصدر: Nature communications [Nat Commun] 2021 Nov 08; Vol. 12 (1), pp. 6436. Date of Electronic Publication: 2021 Nov 08.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Azacitidine/*administration & dosage , Immunotherapy, Adoptive/*methods , Interleukin-3 Receptor alpha Subunit/*immunology , Leukemia, Myeloid/*therapy , Single-Chain Antibodies/*immunology , Xenograft Model Antitumor Assays/*methods, Acute Disease ; Animals ; Cell Line, Tumor ; Cells, Cultured ; Cytotoxicity, Immunologic ; DNA Methylation/drug effects ; Enzyme Inhibitors/administration & dosage ; HEK293 Cells ; HL-60 Cells ; Humans ; Interleukin-3 Receptor alpha Subunit/metabolism ; Kaplan-Meier Estimate ; Leukemia, Myeloid/immunology ; Leukemia, Myeloid/pathology ; Mice, Knockout ; Receptors, Antigen, T-Cell/immunology ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/metabolism ; Mice
مستخلص: Successful treatment of acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) T cells is hampered by toxicity on normal hematopoietic progenitor cells and low CAR T cell persistence. Here, we develop third-generation anti-CD123 CAR T cells with a humanized CSL362-based ScFv and a CD28-OX40-CD3ζ intracellular signaling domain. This CAR demonstrates anti-AML activity without affecting the healthy hematopoietic system, or causing epithelial tissue damage in a xenograft model. CD123 expression on leukemia cells increases upon 5'-Azacitidine (AZA) treatment. AZA treatment of leukemia-bearing mice causes an increase in CTLA-4 negative anti-CD123 CAR T cell numbers following infusion. Functionally, the CTLA-4 negative anti-CD123 CAR T cells exhibit superior cytotoxicity against AML cells, accompanied by higher TNFα production and enhanced downstream phosphorylation of key T cell activation molecules. Our findings indicate that AZA increases the immunogenicity of AML cells, enhancing recognition and elimination of malignant cells by highly efficient CTLA-4 negative anti-CD123 CAR T cells.
(© 2021. The Author(s).)
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المشرفين على المادة: 0 (Enzyme Inhibitors)
0 (Interleukin-3 Receptor alpha Subunit)
0 (Receptors, Antigen, T-Cell)
0 (Receptors, Chimeric Antigen)
0 (Single-Chain Antibodies)
M801H13NRU (Azacitidine)
تواريخ الأحداث: Date Created: 20211109 Date Completed: 20211206 Latest Revision: 20240226
رمز التحديث: 20240226
مُعرف محوري في PubMed: PMC8575966
DOI: 10.1038/s41467-021-26683-0
PMID: 34750374
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-021-26683-0