Chimeric antigen receptor T cell therapy: Revolutionizing cancer treatment

Table 1 Comparative features of major variants of chimeric antigen receptor T cell design components[13-17]

Component	Variant	Key characteristics	Design considerations	Functional impact
ARD	Murine ScFv	High specificity; high immunogenicity; low persistence	Suitable for short-term efficacy	Strong initial response; risk of immune rejection
	Humanized ScFv	Moderate specificity and immunogenicity; improved persistence	Balances efficacy and safety	Enhanced persistence with reduced immunogenicity
	Fully human ScFv	Variable specificity; lowest immunogenicity; high persistence	Ideal for long-term or clinical use	Best suited for chronic and relapsed settings
	Ligand-receptor ARD	Variable specificity; low immunogenicity; high persistence	High safety and efficacy	Targets stress-induced ligands in solid tumors
	TCRm ARD	High specificity; moderate immunogenicity; low persistence	Low safety for chances of off target toxicity; High efficacy	Effective for tumors lacking surface antigens
	VLR	High specificity; high immunogenicity; moderate persistence	Low safety; Promising efficacy	Promising in vitro cytotoxicity
Hinge (spacer) domain	MUC1	Long, no FcγR binding	Effective for membrane-proximal antigens, particularly those with complex glycosylation patterns	modulate immune signaling and enhance tumor-specific responses
	IgG1/4	Varying length; FcγR binding	Effective for membrane-proximal antigens	Requires Fc modification to avoid off-target activation
	CD8α	Short; no FcγR binding	Useful for far membrane epitopes	Enhances synapse formation with minimal off-target risk
	CD28	Short; no FcγR binding	Useful for far membrane epitopes	Promotes stable orientation of CAR
TMD	CD3ζ	TCR-integrated; part of native TCR complex	May synergize with CD3ζ ISD	Low stability; can support natural TCR-like signaling
	CD8α	Stable; commonly paired with CD8α hinge	Improves CAR expression	superior stability and expression
	CD28	Robust membrane anchoring	Common in 2nd-generation CARs	superior stability and expression
	ICOS	High T-cell persistence and function, especially in CD4+ T cells	excellent CAR-T cell tenacity	Efficient anti-cancer application
CSD	CD28	Strong initial T cell activation; IL-2, IL-4, IL-10 secretion; promotes effector T cell differentiation; moderate persistence	Drives effector phenotype	Rapid tumor cytotoxicity with limited duration
	4-1BB (CD137)	Oxidative phosphorylation; prolonged persistence	Promotes memory T cell formation	Sustained activity and long-term tumor control in chronic malignancies

ICOS: Inducible T cell co-stimulator; MUC1: Mucin-1; ARD: Antigen recognition domain; ScFv: Single chain variable fragment; TCRm: T cell receptor-mimicking; VLR: Variable lymphocyte receptors; CAR: Chimeric antigen receptor; TMD: Transmembrane domain; CSD: Co-stimulatory domain.