CRISPR/Cas9-mediated PD-1 and TCR gene-deleted anti-mesothelin CAR-T cells

{
  "id": "MLC-T-ONC-012807",
  "term": "CRISPR/Cas9-mediated PD-1 and TCR gene-deleted anti-mesothelin CAR-T cells",
  "field": "Oncology and biomedicine",
  "definition": "A preparation of human T lymphocytes transduced with a chimeric antigen receptor (CAR) specific for the tumor-associated antigen (TAA) mesothelin and gene-edited with the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 nuclease complex to eliminate endogenous TCR and programmed death 1 (PD-1; PDCD1; CD279; programmed cell death-1) expression, with potential immunostimulating and antineoplastic activities. The CRISPR guide RNA (gRNA) specifically targets and binds to complementary sites on TCRalpha, TCRbeta and PD-1. In turn, Cas9 cleaves these specific DNA sites, thereby disrupting transcription. Upon isolation, transduction, electroporation with TCRalpha, TCRbeta and PD-1 gRNAs, which are complexed to Cas9 RNA to disrupt expression of endogenous TCRalpha, TCRbeta and PD-1, expansion ex vivo, and introduction into the patient, the CRISPR-Cas9-mediated PD-1 and TCR gene-deleted anti-mesothelin CAR T cells recognize and bind to mesothelin-overexpressing tumor cells. This may result in a specific cytotoxic T-lymphocyte (CTL)-mediated killing of mesothelin-positive tumor cells. PD-1, an immune checkpoint receptor expressed on T cells, plays a key role in tumor immune evasion by binding to its ligand programmed death ligand 1 (PD-L1; cluster of differentiation 274; CD274; programmed cell death-1 ligand 1) expressed on tumor cells. By removing PD-1 from T cells, PD-1-mediated signaling is halted which may decrease T-cell exhaustion and may enhance T-cell activity against the mesothelin-expressing tumor cells. Removal of endogenous TCR reduces TCR competition for expression, increases the persistence and function of the expressed transgenic TCR, enhances resistance to T-cell exhaustion and increases T-cell activity. Mesothelin is upregulated on a variety of tumor cell types.",
  "synonyms": [
    "CRISPR-Cas9 mediated PD-1 and TCR gene-knocked-out mesothelin-directed CAR-T cells",
    "CRISPR-Cas9-mediated gene-edited anti-mesothelin CAR-T cells",
    "CRISPR-Cas9-mediated anti-mesothelin CAR T cells",
    "anti-mesothelin CAR-transduced CRISPR-Cas9-edited T cells"
  ],
  "references": [
    "National Cancer Institute Thesaurus"
  ],
  "url": "https://mlchart.com/terminology/oncology/crispr-cas9-mediated-pd-1-and-tcr-gene-deleted-anti-mesothelin-car-t-cells/"
}