Table 2 Comparison of CAR T, NK and macrophages

Intracellular signaling domain

CD3ζ plus a costimulatory domain, CD28, 4-1BB and others

Similar to CAR T structure, but can use NK-specific signaling domains, such as 2B4, DAP10, DAP12.

Similar to CAR T structure, but can use other ITAM-containing signaling domains. Other ligands can be used not to activate phagocytosis, but to modify tumor microenvironment

Cell source

Autologous or MHC-matched allogeneic

Autologous, non-MHC-matched allogeneic or NK cell lines

Autologous. Preclinical studies use iPSCs and cell lines

Off-the-shelf ready-to-use CAR product

Unlikely. Usually autologous. Maybe MHC-matched allogeneic CAR T cells

Yes with NK cell lines. Possibly yes with allogeneic NK cells, but poor recovery with cryopreserve

Theoretically yes with macrophage cell lines. No clinical data.

In vitro expansion

Yes

Yes for autologous NK cells. Cell like can be pre-expanded before transducing.

Yes for autologous macrophages. iPSC and cell lines can be pre-expanded before transducing.

Cytotoxicity mechanisms

CAR-dependent cell killing

Both CAR-dependent and CAR-independent NK-mediated cell kiling

CAR-dependent macrophage-mediated phagocytosis; macrophage-mediated immunostimulatory TIME; macrophage-mediated alteration of tumor microenvironment; macrophages as antigen-presenting cells to stimulate immune response

Cytokine release syndrome and neurotoxicity

Common and often serious

Less common and serious

No clinical data. But expected to be common

Infiltration into tumors

Usually poor

Usually poor

Usually abundant

Clinical experience/trial

Proven efficacy. Five CAR T therapies approved by the FDA

Limited. No approved therapy. At least one trial has been published with superior safety profile

Very limited clinical experience. One CAR macrophage trial is ongoing.