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Table 2 CRISPR/Cas9-mediated gene therapy targets for enhancing TCR and CAR T-cell function

From: CRISPR/Cas9 revitalizes adoptive T-cell therapy for cancer immunotherapy

Cell type Manipulation Gene Protein Cancer Type Summary Advantage Disadvantage
CAR T-cell Universal CAR T-cells TRAC/TRBC TCRαβ Acute Lymphoblastic Leukemia Knocking out endogenous TCR chains reduces the likelihood of GVHD Creates convenient, cheap, and rapid allogeneic CAR T-cells HLA-I elimination could increase reactions from NK cells and lower the efficacy of therapy
B2M Acute Lymphoblastic Leukemia
Immune checkpoint blockade PDCD1 PD-1 Hepatocellular Carcinoma Singular or concurrent knockout of immune checkpoint inhibitors diminishes CAR T-cell exhaustion and increases cytotoxicity and proliferation Creates more active and robust CAR T-cells A potential risk of autoimmunity and off-target effects
CTLA-4 CTLA-4 Acute Lymphoblastic Leukemia
LAG-3 LAG-3 Chronic Myelogenous Leukemia
Fas CD94 Acute Lymphoblastic Leukemia
TGFBR2 TGF-β Squamous Cell Carcinoma
Cytokine production DGKA/DGKZ DGK Glioblastoma Cytokines are pivotal in promoting CAR T-cell activation and function Creates more persistent and cytotoxic CAR T-cell A potential risk of CAR T-cell exhaustion/ limited knock-in efficacy
TCR T-cell Universal TCR T-cells TRAC/TRBC TCRαβ Acute Lymphoblastic Leukemia Knocking out endogenous TCR chains reduces the likelihood of GVHD Creates convenient, cheap, and rapid allogeneic TCR T-cells HLA-I elimination could increase reactions from NK cells and lower the efficacy of therapy
B2M Acute Lymphoblastic Leukemia
Immune checkpoint blockade PD-1 PD-1 Melanoma/ Renal Cell Carcinoma Singular or concurrent knockout of immune checkpoint inhibitors diminishes TCR T-cell exhaustion and increases cytotoxicity and proliferation Creates more active and robust TCR T-cells A potential risk of autoimmunity and off-target effects
CTLA-4 CTLA-4 Bladder Cancer
LAG-3 LAG-3 Chronic Myelogenous Leukemia
TGFBR2 TGF-β Ovarian Cancer
Cytokine production Dhx37 DHX37 Breast Cancer Cytokines are pivotal in promoting CAR T-cell activation and function Creates more active and robust TCR T-cells A potential risk of TCR T-cell exhaustion/ limited knock-in efficacy
Nr2f6 NR2F6 Colon Carcinoma
Gata3 GATA3 Colon Carcinoma
IFNG IFN-γ Melanoma