Preferred Label : Autologous Anti-EGFRvIII 4SCAR-IgT Cells;
NCIt synonyms : PD-1/PD-L1 Antibody-producing T cells (IgT); Autologous EGFRvIII-4SCAR-IgT; EGFRvIII-4SCAR-IgT Cells-producing PD1 and PD-L1 Antibodies; Anti-PD-1/PD-L1-Antibodies-expressing Autologous GBM-specific CAR-T Cells; Autologous Anti-PD-1/Anti-PD-L1 Antibodies-expressing Anti-EGFRvIII CAR T Cells;
NCIt definition : A preparation of autologous T-cells that are genetically modified to express immunoglobulins
(Igs) that target the negative immunoregulatory human cell surface receptor programmed
cell death protein 1 (PD-1; PDCD1; CD279) and programmed death-ligand 1 (PD-L1; CD274)
and are transduced with a replication incompetent, self-inactivating lentiviral vector
expressing a fourth generation chimeric antigen receptor (4SCAR) consisting of a single
chain variable fragment (scFv) targeting anti-epidermal growth factor receptor variant
III (EGFRvIII) that is coupled to the costimulatory signaling domains CD28, CD137,
CD27 and the zeta chain of the T-cell receptor (TCR), and is fused with the suicide
gene inducible caspase 9 (iCasp9), with potential immunostimulating and antineoplastic
activities. Upon administration, autologous anti-EGFRvIII 4SCAR-IgT cells are directed
to and induce selective toxicity in EGFRvIII-expressing tumor cells. iCasp9 consists
of a human FK506 drug-binding domain with an F36V mutation (FKBP12-F36V) linked to
human caspase 9. If the administered T-cells lead to unacceptable side effects, the
chemical homodimerizer AP1903 can be administered. AP1903 binds to the drug binding
FKBP12-F36V domain and induces activation of caspase 9, which results in the apoptosis
of the administered T-cells and enhances safety of this agent. EGFRvIII, a tumor-associated
antigen (TAA) encoded by an in-frame deletion of exons 2-7 in the EGFR gene, is overexpressed
by a variety of cancer cell types and is not expressed by normal, healthy cells. It
plays a key role in tumor cell proliferation, tumor angiogenesis and resistance to
both radio- and chemotherapy. CD28, CD137 and CD27, T-cell surface-associated co-stimulatory
molecules, are required for full T-cell activation and enhance both proliferation
of T-cells and antitumor activity. The anti-PD-1 and anti-PD-L1 antibodies produced
by the T-cells (IgT) bind to PD-1, expressed on T-cells, and its ligand PD-L1 expressed
on cancer cells, respectively. This inhibits PD-1/PD-L1-mediated signaling, prevents
T-cell inhibition and exhaustion, enhances T-cell activation within the tumor microenvironment
(TME) and results in an enhanced T-cell-mediated immune response against and toxicity
in the EGFRvIII-expressing tumor cells.;
NCI Metathesaurus CUI : CL552278;
Origin ID : C150518;
UMLS CUI : C4725796;
Semantic type(s)
- Cell [UMLS semantic type]
- chemical_or_drug_affects_cell_type_or_tissue
- chemical_or_drug_has_mechanism_of_action
- chemical_or_drug_has_physiologic_effect
- concept_is_in_subset
