autologous anti-CEA CAR/HLA-A*02-gated inhibitory receptor/B2M shRNA-expressing T lymphocytes A2B530

A preparation of autologous T lymphocytes from a human leukocyte antigen (HLA)-A*02-positive donor that have been transduced with a lentiviral vector expressing an activating chimeric antigen receptor (CAR) specific for the tumor-associated antigen (TAA) carcinoembryonic antigen-related cell adhesion molecule 5 (CEA or CEACAM5), a leukocyte immunoglobulin-like receptor 1 (LIR-1)-based inhibitory receptor specific for HLA-A*02, and a short hairpin RNA (shRNA) targeting beta-2 microglobulin (B2M), with potential immunomodulating and antineoplastic activities. Upon administration, the autologous anti-CEA CAR/HLA-A*02-gated inhibitory receptor/B2M shRNA-expressing T lymphocytes A2B530 target and bind to CEA-expressing tumor cells, thereby killing CEA-expressing tumor cells. The inhibitory receptor specific for HLA-A*02 acts as a safety switch that blocks the killing of HLA-A*02-positive CEA-expressing normal cells. HLA-A*02 is expressed on normal cells but not on tumor cells due to loss of heterozygosity (LOH). The B2M shRNA disrupts the expression of the B2M component of the HLA class I molecule. CEA, a member of the CEA family of proteins, plays a key role in cell migration, cell invasion and cell adhesion, and is overexpressed by a variety of cancer types.