Table 2.

Advantages and disadvantages of alternative immune effector cells as platforms for CAR engineering

Alternative immune effector cell	Advantages	Disadvantages	Safety profile
NK cell	Multiple innate activating receptors that can mediate killing	Low persistence in the absence of cytokine	In early clinical results of CAR-NK cells:
	Can harness KIR-ligand mismatch and “missing self” to reduce risk of relapse	Numerically few necessitating ex vivo expansion	-No GVHD
	Multiple mechanisms of cytotoxicity	Suboptimal trafficking and penetration into solid tumors	-No CRS
	No need for previous antigen priming		-No ICANS
	Rapid tumor killing
iNKT	Innate and adaptive features	Can have immunosuppressive properties (Th2, Th17)	Limited clinical data with iNKT-CAR NK cells; reports in 2 patients showed no toxicity
	Invariant TCR recognizes lipid antigens presented by CD1d	Numerically few requiring ex vivo expansion	In non–CAR-engineered cells:
			-No GVHD
			-No toxicities
γδ T cells	Links innate and adaptive immune systems	Can have immunosuppressive properties (γδ T17, Vδ1 γδ T cells, γδ Treg)	No clinical data with CAR γδ T cells
	MHC independent γδ TCR	Numerically few necessitating ex vivo expansion	In non–CAR-engineered cells:
	Cross-present antigens to αβ T cells		No GVHD
			No toxicities
Macrophages	Good penetration into solid tumors	Can have immunosuppressive properties (M2)	No clinical data with CAR macrophages
	Mediates phagocytosis and cytotoxicity	Numerically few necessitating ex vivo expansion	In non–CAR-engineered cells:
	Cross present antigens to αβ T cells		No GVHD
			No toxicities
CIK	Multiple killing mechanisms including MHC-dependent and MHC-independent	Heterogeneous products	No clinical data with CAR CIK
		Numerically few necessitating ex vivo expansion	In non–CAR-engineered cells:
			Lower GVHD risk than T cells60