Table 1 Specific gene editing can improve the characteristics of CAR T/NK cells
From: Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies
Gene(s) | method | Cell type | T/NK cell Improvement | Reference |
|---|---|---|---|---|
TET2 | Disruption by CAR transgene | T cells | TET2 dysfunction results in the production of effective CAR T cells, which have the characteristics of short-lived memory cells that can mediate effector responses, as well as long-lived, persistent memory cells | [43] |
UBR1 | Disruption by CAR transgene | T cells | A member of the ubiquitin ligase family is involved in protein degradation and contributes to the formation of long-term persisting clones | [45] |
STAT5B and BACH2 | HIV-1 insertional activation | T regulatory and T central memory cells | Genes commonly targeted as insertion sites by HIV-1, generate chimeric mRNAs that are enriched in T regulatory and T central memory cells, and increase proliferation and survival rate without compromising function | |
TRAC (CD52, dCK) | Disruption by CAR transgene or by TALEN | T cells | Reduces tonic signaling, avoids an accelerated T cell differentiation and exhaustion, improves the therapeutic efficacy, renders T cells resistant to simultaneous infusions of lymphodepleting regimens, and controls the rate of elimination via host versus graft reactions | |
PD-1 (B2M, TRBC, TIM-3, LAG-3, A2AR) | Disruption by multiplex genome editions | T cells | Generate universal CAR T cells resistant to PD-1 inhibition and improves antitumor efficacy | |
TOX/TOX2 | Disruption /CAR-T cells generated from donor TOX and TOX2 DKO (-/-) mice | CD8+ T cells | CAR TILs deficient in both TOX and TOX2 are more effective than wild-type (WT) in suppressing tumor growth and prolonging the survival of tumor-bearing mice | [57] |
NR4A | Disruption | CD8+ T cells | CAR T cells that are lacking all three Nr4a TFs (Nr4aTKO) promote tumor regression and prolong the survival rate of tumor-bearing mice and reduce hyporesponsiveness of CD8+ T cells | [58] |
P38 | Disruption /using p38i in culture media | T cells | Pharmacological inhibition of p38 improved the efficacy of mouse anti-tumor T cells and enhanced the functionality of human tumor-reactive and gene-engineered T cells | [59] |
HPK1 | Disruption by CRISPR/Cas9 | T cells | less exhausted and more active and proliferative T cells | [60] |
IFN-γ signaling genes | Disruption | NK cells | Known to improve NK cell function | [61] |
CD5 | Disruption by CRISPR/Cas9 | Jurkat cells | CAR T cells deficient in the expression of CD5 do not mediate fratricide | [62] |
shp-2 | Disruption by CRISPR/Cas9 | NK-like YT cells | Increases the cytotoxicity of effector NK-like YT cells | [63] |
TGFBR2 (FOXP3) | Disruption by CRISPR/Cas9 | NK cells T cells | Modified NK cells become TGFβ1-resistant, exhibit increased proliferation and effector cytokine production, long-term persistence, as well as increased ability to mediate eradication of aggressive tumor | |
HPRT1 | Disruption by CRISPR/Cas9 | Primary NK cells | Modified NK cells become resistant to TGFβ1 | [64] |
ADAM17 and PDCD1 | Disruption by CRISPR/Cas9 | Primary NK cells | Significantly improves activity, cytokine production, and tumor cell cytotoxicity | [41] |
CISH | Disruption by CRISPR-Cas9 | Cord blood NK cells | Targeting a cytokine checkpoint further enhances the antitumor activity of IL-15-secreting armored CAR-NK cells by promoting their metabolic fitness and antitumor activity | [67] |
TIGIT | Blockade | NK cells | TIGIT inhibits NK cell cytotoxicity by opposing CD226, so its blockade can lead to persistent therapeutic benefits | |
SHP-1 | Blockade | T cells | Better control of PD-L1 expressing tumor growth alongside increasing the infiltration rate of CAR T cells into the tumor milieu | |
A2ARs | A2AR antagonists or targeting of A2AR using shRNA | T cells | Inhibits T cell activation through the cAMP-PKAI-CSK pathway; therefore, its inhibition enhances anti-tumor effects mediated by CAR T cells | [72] |
ROS family | Disruption | T cells | Causes DNA oxidative damage | [73] |
HDACi | Augmentation | T cells and NK cells | Can lead to survival potency in CAR T cells along with immunoradiotherapy | |
p53 | p53-KO T cells from donor transgenic mice | T cells | As a tumor suppressor protein cause upregulation of PD-1 and its PD-L1 and with redox activity may enhance T cell radioresistance | [76] |
BCL2 family | Disruption | T cells | Prevents the intrinsic apoptosis and synergistically enhances the persistence of T cells, reduces their sensitivity to Fas-induced apoptosis, alongside increasing their survival and antitumor activity | |
SMAD3 | Knocking down | NK cells | Its silencing improves NK cell cytotoxicity in solid tumors | [79] |
CCR5 | Disruption by ZNF | T cells | A safe harbor locus | [80] |
CD56 | Augmentation | T cells | The homophilic interaction between intercellular CD56 correlates with enhanced infiltration of CAR T cells, increased secretion of INF-γ, and prolonged survival of CAR T cells. Moreover, ectopically expressed CD56 promotes CAR T cell survival and antitumor responses | [81] |
CD73 | Blockade | NK cells | Increases homing of NKG2D-CAR NK cells to tumor sites and improves antitumor responses in animal models | [82] |