autologous iC9-GD2-CAR-expressing VZV-specific T lymphocytes

Genetically modified, autologous varicella zoster virus (VZV)-specific T-lymphocytes transduced with a retroviral vector encoding a chimeric antigen receptor (CAR) specific for the disialoganglioside GD2, which contains the signaling domains for the co-stimulatory molecules CD28 and CD134 (OX-40), and the suicide gene, inducible caspase 9 (iCasp9 or iC9), with potential immunomodulating and antineoplastic activities. Upon intravenous administration, iC9-GD2-CD28-OX40-expressing T lymphocytes target the GD2 antigen on tumor cells for selective toxicity against GD2-expressing tumor cells. iCasp9 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 T cells lead to unacceptable side effects, the chemical homodimerizer AP1903 can be administered, which binds to the FKBP12-F36V drug binding domain, activates caspase 9, and results in apoptosis of the administered T-cells. Expression of the iCasp9 gene in T cells for adoptive transfer increases safety and broadens the scope for their clinical applications. The tumor-associated antigen GD2 is overexpressed on the surface of almost all tumors of neuroectodermal origin. OX40 and CD28, both T-cell surface-associated co-stimulatory molecules, are required for full T-cell activation. An additional VZV vaccine can be administered to increase T-cell activity.