Autologous Anti-B7-H3 CAR-iC9-expressing T-lymphocytes
autologous anti-b7-h3 car-ic9-expressing t-lymphocytes
A preparation of autologous T-lymphocytes that have been genetically modified to express a chimeric antigen receptor (CAR) specific for the immunoregulatory protein B7-homologue 3 (B7-H3, CD276) and the suicide gene inducible caspase 9 (iCasp9 or iC9), with potential immunostimulating and antineoplastic activities. Upon administration, autologous anti-B7-H3 CAR-iC9-expressing T-lymphocytes specifically target and bind to B7-H3-expressing tumor cells, resulting in tumor cell lysis. B7-H3, a type I transmembrane protein and a member of the B7 co-stimulatory protein superfamily, is overexpressed on certain tumor cell types and on various immune cells. It is a negative regulator of T-cell activation and its overexpression plays a key role in tumor cell invasion and metastasis. The iCasp9 safety switch consists of a full-length caspase 9, including its caspase recruitment domain, linked to a human FK506 drug-binding domain with an F36V mutation (FKBP12-F36V). If the administered CAR T-cells lead to unacceptable side effects, the chemical homodimerizer AP1903 can be administered. AP1903 binds to the FKBP12-F36V drug-binding domain, activates caspase 9 and results in apoptosis of the administered CAR T-cells.