Table 5 Current status of CAR macrophage studies
From: CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy
References | Macrophage source | Target antigens | Extracellular/ Intracellular domains | Major findings |
|---|---|---|---|---|
Morrisey et al [97] | J774A.1 Macrophages | CD19, CD22 | Extra: scFv Intra: Megf10, FcγR, CD3ζ, FcγR + PI3K | 1. ITAM-containing CD3ζ, FcRγ and Megf10 intracellular domains have comparable phagocytic efficiency 2. Addition of a PI3K-recruiting domain enhances phagocytosis of whole cells 3. Most CAR macrophages exert trogocytosis 4. Addition of anti-CD47 antibody enhances phagocytosis |
Zhang L. et al [104] | induced pluripotent stem cells (iPSCs) | CD19 | Extra: scFv Intra: CD86 + FcγRI | 1. iPSCs can be used to generate CAR macrophages 2. iPSCs CAR macrophages (CAR-iMACs) possess M2 phenotype 3. Engagement of target cells titls toward M1 differentiation 4. CAR-iMACs can expand, persist and exert anti-tumor activities in vivo |
Zhang W. et al. [105] | Raw264.7 monocyte/ macrophages | HER2 | Extra: scFv Intra: CD147 | 1. CAR-147 upregulates MMP expression in vitro and in vivo; 2. CAR-147 does not exhibit phagocytosis; 3. CAR-147 decreases collagen content, induces CD3+ T cell infiltration and inhibits tumor growth. |
Niu et al. [99] | Raw264.7 monocyte/ macrophages | CCR7 | Extra: CCL19 Intra: TLR2, TLR4, TLR6, MerTK, 4-1BB-CD3ζ | 1. CAR-M (MerTK) has the most efficient cell killing and phagocytosis in vitro compared to CAR-M with other intracellular domains; 2. At high dose, CAR-M also induces hair and body weight loss as CCR7 is also expressed at hair follicles and intestinal villi; 3. CAR-M (MerTK) suppresses tumor growth, prolongs survival, inhibits cancer metastasis in mice with little toxicity; 4. CAR-M (MerTK) significantly induces CD3+ T cell infiltration, decreases PD-L1-positive cells, and increases pro-inflammatory cytokine production in tumors. |
Klichinsky et al [98] | Human THP-1 cell line | HER2 | Extra: scFv Intra: CD3ζ | 1. A replication-incompetent adenoviral vector can highly efficiently deliver CAR to human macrophages; 2. Adenoviral injection induces M1 differentiation and pro-inflammatory tumor microenvironment; 3. Adenovirus-transduced CAR macrophages can cross-present tumor-derived antigens and more efficiently activate T cells 4. Adenovirus-transduced CAR macrophages significantly prolongs survival and decreases metastasis of tumor-carrying mice. |