Targeting of tumor cells expressing the prostate stem cell antigen (PSCA) using genetically engineered T‐cells

BACKGROUND Curative therapeutic options for minimal residual disease or advanced tumor stages in prostate cancer (PCa) are still missing. Adoptive transfer of cytotoxic T-cells that have been polyclonally rendered tumor-specific by genetic engineering appears to be a promising immunotherapeutic strategy. Among the numerous prostate tissue/tumor antigens identified during the last years, the “prostate stem cell antigen” (PSCA) is an attractive immunotherapeutic target. It is broadly expressed on the surface of primary PCa cells as well as on PCa metastases. METHODS To generate a chimeric T-cell receptor (TCR) recognizing PSCA, a monoclonal anti-PSCA antibody was raised and a single-chain fragment (scFv) was prepared. The resulting anti-PSCA scFv 7F5 was fused to the β2 constant region derived from the β-chain of a TCR and to the CD3ζ-signaling domain. RESULTS The chimeric α-PSCA-β2/CD3ζ-TCR, expressed in Jurkat cells, was phosphorylated in the ITAMs of the CD3-zeta chain upon cross-linking by insolublized PSCA. When transduced into a mouse cytotoxic T-cell line, the chimeric receptor specifically activated cytotoxicity against PSCA-positive tumor cells. CONCLUSIONS We developed a functional chimeric TCR against PSCA for treatment of PCa. The chimeric α-PSCA-β2/CD3ζ-TCR might now be used for arming human cytotoxic T-cells for further studies towards a clinical treatment of PCa. Prostate 67: 1121–1131, 2007. © 2007 Wiley-Liss, Inc.