Preferred Label : Chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes;
NCIt synonyms : Chlorotoxin-CD28-CD3z-CD19t-expressing CAR T-cells;
NCIt definition : A preparation of genetically modified T-lymphocytes transduced with a lentiviral vector
expressing a chimeric antigen receptor (CAR) comprised of a CD28 co-stimulatory signaling
domain fused to the zeta chain of the TCR/CD3 complex (CD3zeta), a truncated form
of CD19 (CD19t), an immunoglobulin (Ig) G4-Fc (EQ) spacer, and a peptide derived from
chlorotoxin (CLTX), with potential imaging and antineoplastic activities. Upon administration,
chlorotoxin (EQ)-CD28-CD3zeta-CD19t-expressing CAR T-lymphocytes are re-directed to
specific tumor cells in the brain inducing selective toxicity in these tumor cells.
CLTX, a 36-amino acid peptide found in the venom of the deathstalker scorpion (Leiurus
quinquestriatus) and a chloride channel blocker, preferentially binds to glioma (and
other neuroectodermal origin) cells via membrane bound forms of the endopeptidase
matrix metalloproteinase-2 (MMP-2). This may direct the T-lymphocytes to and induce
selective toxicity in MMP-2-expressing tumor cells. Additionally, binding to MMP-2
on glioma cells may both interfere with transmembrane chloride exchange and inhibit
proteolytic extracellular matrix remodeling by MMP-2, which may further limit the
spread of these tumor cells. MMP-2 is specifically upregulated in gliomas and related
cancers, but is not normally expressed in brain. The CD28 co-stimulatory molecule
signaling domain enhances activation and signaling; its inclusion may increase proliferation
of T-cells and antitumor activity compared to the inclusion of the CD3 zeta chain
alone. IgG4-Fc (EQ) contains two point mutations in its spacer region which prevents
recognition of the CAR by Fc receptors (FcRs) without altering the ability of the
CAR to mediate antigen-specific lysis. CD19t, which lacks the cytoplasmic signaling
tail, provides a non-immunogenic surface marker that allows for accurate measurement,
efficient cell tracking and/or imaging of the therapeutic T-cells in vivo following
adoptive transfer. Additionally, co-expression of CD19t functions as a suicide switch
via clinically available antibodies or immunotoxins which can be used to selectively
eliminate the genetically modified cells.;
NCI Metathesaurus CUI : CL972048;
Origin ID : C167056;
UMLS CUI : C5238225;
Semantic type(s)
- Cell [UMLS semantic type]
- concept_is_in_subset
- has_target
