Paasch, Daniela and Meyer, Johann and Stamopoulou, Andriana and Lenz, Daniela and Kuehle, Johannes and Kloos, Doreen and Buchegger, Theresa and Holzinger, Astrid and Falk, Christine S. and Kloth, Christina and von Kaisenberg, Constantin S. and Abken, Hinrich and Schambach, Axel and Lachmann, Nico and 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): 994. ISSN , 2073-4409
Full text not available from this repository. (Request a copy)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: | Article |
|---|---|
| Uncontrolled Keywords: | CHIMERIC ANTIGEN RECEPTORS; T-CELLS; ADOPTIVE IMMUNOTHERAPY; CD28 COSTIMULATION; KILLER-CELLS; ACTIVATION; SECRETION; MONOCYTES; TRIAL; DAP12; chimeric antigen receptors; macrophages; cancer; hematopoietic stem cells; solid tumors; cancer immunotherapy; phagocytosis |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 29 Feb 2024 16:05 |
| Last Modified: | 29 Feb 2024 16:05 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58495 |
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