从造血干细胞及祖细胞体外生成用于肿瘤治疗的 CAR 巨噬细胞

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 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 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 s ex vivo.

Our data showed successful CAR expression in cord blood (CB)-derived HSPCs, with considerable cell expansion during differentiation to CAR M s. HSPC-derived M s showed typical M morphology, phenotype, and basic anti-bacterial functionality. CAR M s targeting the carcinoembryonic antigen (CEA) and containing either a DAP12- or a CD3 -derived signaling domain showed antigen redirected activation as they secreted pro-inflammatory cytokines specifically upon contact with CEA + target cells.

In addition, CD3 -expressing CAR M s exhibited significantly enhanced phagocytosis of CEA + HT1080 cells.

Our data establish human HSPCs as a suitable cell source to generate functional CAR M s and further support the use of CAR M s in the context of solid tumor therapy.