Table 2.

Knockout of negative regulators in CAR T cells improves antitumor activity

Negative regulators	Name	Malignancy	Genome editing tool	Function	Reference(s)
Immune checkpoint molecules	PD-1	ALL, CML, TNBC, HCC, Glioma	CRISPR-Cas9, TALEN, AAV–Cpf1	Improved cytokine production, infiltration and persistence of CAR T cells; enhanced tumor clearance	[113–119]
	CTLA-4	NMIBC, CML	CRISPR-Cas9	Improved CAR T cell function	[119, 120]
	LAG3	Burkitt lymphoma, CML	CRISPR-Cas9	Improved CAR T cell function	[121]
Transcription factors	NR4A	Melanoma, Thymoma, COAD	—	Promoted tumor regression	[122]
	TOX	Melanoma, COAD	shRNAs	Augmented antitumor responses	[123]
Metabolic molecules	DGKs	GBM	CRISPR-Cas9	Increased TCR signaling in CAR T cells; enhanced CAR T cell effector function	[124]
Apoptotic genes	Fas	ALL, CML	CRISPR-Cas9	Increased tolerance of CAR T cells to apoptosis	[119]

AAV adeno-associated virus, ALL acute lymphoblastic leukemia, CAR chimeric antigen receptor, COAD colon adenocarcinoma, CML chronic myeloid leukemia, shRNA short hairpin RNA, NMIBC non-muscle invasive bladder cancer, TALEN transcription activator-like effector nuclease, TNBC triple-negative breast cancer, HCC hepatocellular carcinoma, GBM glioblastoma