autologous anti-MSLN CAR/HLA-A*02-gated inhibitory receptor/B2M shRNA-expressing T lymphocytes A2B694

A preparation of autologous T lymphocytes that have been transduced with a lentiviral vector expressing an activating chimeric antigen receptor (CAR) specific for the tumor-associated antigen (TAA) mesothelin (MSLN), a leukocyte immunoglobulin-like receptor 1 (LIR-1)-based inhibitory receptor specific for human leukocyte antigen (HLA)-A*02 (HLA-A*02), and a short hairpin RNA (shRNA) targeting beta-2 microglobulin (B2M; beta2M), with potential immunomodulating and antineoplastic activities. Upon administration, the autologous anti-MSLN CAR/HLA-A*02-gated inhibitory receptor/B2M shRNA-expressing T lymphocytes A2B694 target and bind to MSLN-expressing tumor cells, thereby killing MSLN-expressing tumor cells that have loss of heterozygosity (LOH) for HLA-A*02 protein. The inhibitory receptor specific for HLA-A*02 acts as a self-regulated safety switch that blocks the killing of HLA-A*02-positive MSLN-expressing normal, healthy cells. HLA-A*02 is expressed on normal cells but not on tumor cells due to LOH. The B2M shRNA disrupts the expression of the B2M component of the HLA class I molecule. MSLN, a cell surface glycoprotein involved in cell adhesion, is overexpressed in a variety of cancer cell types.