Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock


Ex Vivo Generation of CAR Macrophages from Hematopoietic Stem and Progenitor Cells for Use in Cancer Therapy.


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 (MPhis) 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 MPhis. 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 MPhis ex vivo. Our data showed successful CAR expression in cord blood (CB)-derived HSPCs, with considerable cell expansion during differentiation to CAR MPhis. HSPC-derived MPhis showed typical MPhi morphology, phenotype, and basic anti-bacterial functionality. CAR MPhis targeting the carcinoembryonic antigen (CEA) and containing either a DAP12- or a CD3zeta-derived signaling domain showed antigen redirected activation as they secreted pro-inflammatory cytokines specifically upon contact with CEA+ target cells. In addition, CD3zeta-expressing CAR MPhis exhibited significantly enhanced phagocytosis of CEA+ HT1080 cells. Our data establish human HSPCs as a suitable cell source to generate functional CAR MPhis and further support the use of CAR MPhis in the context of solid tumor therapy.

Authors: Paasch D, Meyer J, Stamopoulou A, Lenz D, Kuehle J, Kloos D, Buchegger T, Holzinger A, Falk CS, Kloth C, von Kaisenberg CS, Abken H, Schambach A, Lachmann N, Morgan M, Moritz T,
Journal: Cells . 2022 Mar 15;11(6):994. . doi:10.3390/cells11060994
Year: 2022
PubMed: PMID: 35326445 (Go to PubMed)