Designing Chimeric Antigen Receptors for Myeloid Immune Cells.

Chimeric antigen receptor (CAR) myeloid cells are a promising potential alternative to CAR T-cells for solid tumor therapies. Myeloid CAR therapies have been tested in preclinical studies by either transferring established CD3-based T-cell CARs into myeloid cells, or by designing myeloid-specific signaling domains. While ITAM-based myeloid receptors (e.g., Fc-receptors) were often outperformed by classic CD3ζ-designs, toll-interleukin-1 receptor (TIR) and Mer receptor tyrosine kinase (MerTK) have shown promise for improving myeloid-specific cell activation. Addition of CD147 to stimulate matrix-metalloproteinase production and of cytokine genes (e.g. interferon γ) may further improve the efficacy of CAR-myeloid cells in the tumor immune microenvironment. While most work focused on CAR monocytes and macrophages, CAR-DC cells are also being studied as tumor vaccines in preclinical and early clinical phases. Lastly, even though CAR neutrophils are disadvantaged by a short lifespan, they could become viable by transfusing them as undifferentiated myeloid progenitors instead of effector cells. Here, we summarize the status of preclinical and clinical research on different CAR myeloid strategies, compare receptor designs, outline gaps in knowledge, conflicting results, and approaches for future preclinical studies that will allow translation of these technologies to the clinic.