Preferred Label : Autologous HER2-targeted Dual-switch CAR-T Cells BPX-603;
NCIt synonyms : Autologous Dual-switch GoCAR-T Cells BPX-603; Autologous HER2-CAR-T Cells BPX-603; Autologous CAR-T Cells BPX-603;
NCIt definition : A preparation of autologous T-lymphocytes that express a chimeric antigen receptor
(CAR) for the human epidermal growth factor receptor 2 (EGFR2; HER2; HER-2) and a
dual-switch composed of chemical inducer of dimerization (CID)-inducible co-activation
domain MyD88/CD40 (inducible MC; iMC), in which both the MyD88 and CD40 lack their
extracellular domains, and an inducible caspase 9 (iCasp9) safety switch (CaspaCIDe),
consisting of the CID-binding domain coupled to the signaling domain of caspase-9,
with potential immunomodulating and antineoplastic activities. Upon administration
of autologous HER2-targeted dual-switch CAR-T cells BPX-603, the T-cells target and
bind to HER2-expressing cancer cells. Upon subsequent administration of the CID agent
rimiducid (AP1903), this agent targets and binds to the drug binding domain of iMC
and activates iMC, which leads to the activation of both CD40- and MyD88-mediated
signal transduction pathways. This allows for enhanced T-cell proliferation, persistence
and resistance to T-cell exhaustion and upregulation of immunomodulatory cytokines
within the tumor microenvironment (TME). This increases the anti-tumor activity of
the administered T-cells, compared to T-cells without the iMC activation-switch. As
these T-cells are engineered to only be fully activated by binding to both the HER2
antigen and rimiducid, T-cell proliferation, activity and toxicity can be controlled
by adjusting the dose of rimiducid, thereby preventing uncontrolled T-cell activation
which increases the safety of the administered T-cells. The binding of rimiducid to
the CID binding domain of iCasp9 results in the cross-linking and dimerization of
iCasp9, which causes its activation. This results in the induction of caspase-mediated
apoptosis of the transduced cells and allows for the removal of inappropriately activated
cells, thereby preventing toxicity of the administered cells. HER2, a tumor-associated
antigen (TAA), plays a key role in tumor cell proliferation and tumor vascularization.;
Molecule name : BPX-603; BPX 603;
NCI Metathesaurus CUI : CL1642773;
Origin ID : C176990;
UMLS CUI : C5447541;
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
- has_target
