Paasch, Daniela, Meyer, Johann, Stamopoulou, Andriana, Lenz, Daniela, Kuehle, Johannes, Kloos, Doreen, Buchegger, Theresa, Holzinger, Astrid, Falk, Christine S., Kloth, Christina, von Kaisenberg, Constantin S., Abken, Hinrich ORCID: 0000-0002-4302-3240, Schambach, Axel, Lachmann, Nico ORCID: 0000-0002-4245-1497, Morgan, Michael and Moritz, Thomas (2022). Ex Vivo Generation of CAR Macrophages from Hematopoietic Stem and Progenitor Cells for Use in Cancer Therapy. Cells, 11 (6). BASEL: MDPI. ISSN 2073-4409

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Abstract

Chimeric antigen receptor (CAR) T-cell therapies have shown impressive results in patients with hematological malignancies; however, little success has been achieved in the treatment of solid tumors. Recently, macrophages (M phi s) were identified as an additional candidate for the CAR approach, and initial proof of concept studies using peripheral blood-derived monocytes showed antigen-redirected activation of CAR M phi s. However, some patients may not be suitable for monocyte-apheresis, and prior cancer treatment regimens may negatively affect immune cell number and functionality. To address this problem, we here introduce primary human hematopoietic stem and progenitor cells (HSPCs) as a cell source to generate functional CAR M phi s ex vivo. Our data showed successful CAR expression in cord blood (CB)-derived HSPCs, with considerable cell expansion during differentiation to CAR M phi s. HSPC-derived M phi s showed typical M phi morphology, phenotype, and basic anti-bacterial functionality. CAR M phi s targeting the carcinoembryonic antigen (CEA) and containing either a DAP12- or a CD3 zeta-derived signaling domain showed antigen redirected activation as they secreted pro-inflammatory cytokines specifically upon contact with CEA(+) target cells. In addition, CD3 zeta-expressing CAR M phi s exhibited significantly enhanced phagocytosis of CEA(+) HT1080 cells. Our data establish human HSPCs as a suitable cell source to generate functional CAR M phi s and further support the use of CAR M phi s in the context of solid tumor therapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Paasch, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Meyer, JohannUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stamopoulou, AndrianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lenz, DanielaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuehle, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloos, DoreenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buchegger, TheresaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzinger, AstridUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Falk, Christine S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloth, ChristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Kaisenberg, Constantin S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abken, HinrichUNSPECIFIEDorcid.org/0000-0002-4302-3240UNSPECIFIED
Schambach, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lachmann, NicoUNSPECIFIEDorcid.org/0000-0002-4245-1497UNSPECIFIED
Morgan, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moritz, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-681694
DOI: 10.3390/cells11060994
Journal or Publication Title: Cells
Volume: 11
Number: 6
Date: 2022
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2073-4409
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHIMERIC ANTIGEN RECEPTORS; T-CELLS; ADOPTIVE IMMUNOTHERAPY; CD28 COSTIMULATION; KILLER-CELLS; ACTIVATION; SECRETION; MONOCYTES; TRIAL; DAP12Multiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68169

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