autologous ALPG/ALPP-targeted anti-MSLN CAR-Fas/PTPN2 shRNA-miR-expressing T lymphocytes AB-1015

A preparation of autologous T lymphocytes that have been modified to encode a genetic circuit consisting of a priming receptor that induces the expression of a chimeric antigen receptor (CAR) specific for the tumor-associated antigen (TAA) mesothelin (MSLN) upon binding to the TAAs alkaline phosphatase (ALP) isozymes ALP germ cell type (ALPG; GCAP) or ALP placental type (ALPP; placental ALP; PLAP), and a dual microRNA-adapted short hairpin RNA (shRNA-miR) targeting Fas (FAS; CD95; APO-1; tumor necrosis factor receptor superfamily member 6; TNFRSF6) and tyrosine-protein phosphatase non-receptor type 2 (PTPN2), with potential immunomodulating and antineoplastic activities. Upon administration, the autologous ALPG/P-targeted anti-MSLN CAR-Fas/PTPN2 shRNA-miR-expressing T lymphocytes AB-1015 target and bind to ALPG/P-expressing tumor cells and induce the expression of anti-MSLN CAR, thereby killing ALPG/P- and MSLN-expressing tumor cells. The downregulation of the expression of Fas by the shRNA-miR prevents Fas-mediated apoptosis of the AB-1015 T cells in the tumor microenvironment (TME). The downregulation of the expression of PTPN2 enhances AB-1015 T-cell expansion and anti-tumor T-cell immune responses. ALPG and ALPP, overexpressed in a variety of cancer cell types, play important roles in tumor cell proliferation and tumor growth. MSLN, a cell surface glycoprotein involved in cell adhesion, is overexpressed in a variety of cancer cell types.