Definition

A preparation of T cells that are genetically engineered to express fourth generation chimeric antigen receptors (4SCARs) targeting the three tumor-associated antigens (TAAs) prostate-specific membrane antigen (PSMA), disialoganglioside (GD2), and the immune checkpoint molecule protein B7-homologue 3 (B7-H3, CD276), coupled to the costimulatory signaling domains CD28, CD137, CD27 and the zeta chain of the T-cell receptor (CD3zeta; CD3z), and fused with the suicide gene inducible caspase 9 (iCasp9), with potential immunostimulating and antineoplastic activities. Upon administration, the anti-GD2/PSMA/CD276-4SCAR-expressing T cells are directed to and induce selective toxicity in GD2-, PSMA- and CD276-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. PSMA, a type II transmembrane protein, is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells as well as a variety of other solid tumors, including brain tumor, neuroblastoma (NB) and some lymphoma tumor tissues. CD276, a type I transmembrane protein and a member of the B7 co-stimulatory protein superfamily, is highly expressed on many solid tumors including NB. It is a negative regulator of the T-cell activation and plays a key role in tumor evasion. GD2 is overexpressed on the surface of NB cells and by other neuroectoderm-derived neoplasms, while it is minimally expressed on normal cells. 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.