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Table 2 Knockout of negative regulators in CAR T cells improves antitumor activity

From: Gene modification strategies for next-generation CAR T cells against solid cancers

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

[113,114,115,116,117,118,119]

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]

  1. 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