Table 2.

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

Alternative immune effector cellAdvantagesDisadvantagesSafety 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  
Alternative immune effector cellAdvantagesDisadvantagesSafety 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  
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