autologous anti-glypican-3 CAR-IL-15-iC9-expressing T lymphocytes

A preparation of T lymphocytes that have been genetically modified to express a chimeric antigen receptor (CAR) specific for glypican-3 (GPC3) and express interleukin-15 (IL-15) and the suicide gene, inducible caspase 9 (iCasp9 or iC9), with potential immunostimulating and antineoplastic activities. Upon administration, anti-GPC3-CAR-IL-15-iC9-expressing T lymphocytes specifically target and bind to GPC3-expressing tumor cells, resulting in tumor cell lysis. GPC3, a heparan sulfate proteoglycan and a member of the glypican family, is overexpressed on certain tumor cell types while minimally expressed on normal, healthy cells; GPC3 plays an important role in cellular proliferation and differentiation. IL-15 is a pro-survival cytokine that potentiates, in addition to promoting T-cell proliferation and persistence, the immune response against tumor cells. 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.