Table 4.

Roadblocks and challenges in CAR T cell therapy.

Challenges	Solutions	Reference
Antigen selection and off-tumor toxicity	Using tumor-associated antigens (TAAs) as target antigens in CAR T cell therapy	[183,185,187]
	Control of CAR T cell therapy associated toxicity, including: iCARs, multivalent CARs, and implementation of suicide genes	[190,191,192]
Tumor heterogeneity and antigen loss	Using armored CAR T cells	[198]
	Using bystander killing approach	[197]
	Using drugs, especially epigenetic drugs to up-regulate TAAs	[202]
	Using multivalent CAR T cells	[194]
Insufficient infiltration and penetration	Using CAR T cells that express corresponding chemokine receptors (Suggestion)	[210]
	Using engineered CAR T cells expressing heparinase or other enzymes that can degrade ECM components	[212]
Immunosuppressive tumor microenvironment	Using CAR T cells resistant to immunosuppressive molecules including adenosine	[216,217]
	Using inhibitory receptor knock out/down CAR T cells	[215]