dimerizing agent-regulated immunoreceptor complex-expressing CD33-specific autologous CAR T cells SC-DARIC33

A preparation of equal amounts of autologous CD4-positive and CD8-positive T lymphocytes transduced with a lentiviral vector expressing a chimeric antigen receptor (CAR) specific for the tumor-associated antigen (TAA) CD33 and genetically modified to express a Dimerizing Agent Regulated Immunoreceptor Complex (DARIC), with potential immunomodulating and antineoplastic activities. Upon transfusion of the DARIC-expressing CD33-specific autologous CAR T cells SC-DARIC33 and followed by intermittent low dose rapamycin administration, rapamycin binds to DARIC and activates the T cells when binding to CD33-expressing tumor cells, thereby inducing selective toxicity in CD33-expressing tumor cells. CD33 is expressed on normal non-pluripotent hematopoietic stem cells and on myeloid leukemia cells. The ability of rapamycin to control the activity of the DARIC cells may help control the toxicity of the CAR T cells, prevent T-cell exhaustion and may help them last longer in vivo. Using the DARIC platform, the antigen recognition and signaling functions of a CAR are separated into two distinct polypeptides and engineered to contain the two interacting and dimerization domains, FK506-binding protein (FKPB12) and FKBP12-rapamycin-binding (FRB) protein. In the absence of the dimerizing drug rapamycin, the CAR T cells lack signaling activity upon antigen recognition and binding. The administration of the dimerizing agent enables the two DARIC subunits to interact and thereby allows for the CAR T cells to fully function and activate their signaling abilities upon antigen recognition.