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 beta2 constant region derived from the beta-chain of a TCR and to the CD3zeta-signaling domain.


RESULTS
The chimeric alpha-PSCA-beta2/CD3zeta-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 alpha-PSCA-beta2/CD3zeta-TCR might now be used for arming human cytotoxic T-cells for further studies towards a clinical treatment of PCa.
Morgenroth
Agnieszka
A
Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
Cartellieri
Marc
M
Schmitz
Marc
M
Günes
Serap
S
Weigle
Bernd
B
Bachmann
Michael
M
Abken
Hinrich
H
Rieber
Ernst Peter
EP
Temme
Achim
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D000951:Antigens, Neoplasm; D002460:Cell Line; D045744:Cell Line, Tumor; D002678:Chimera / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D058851:GPI-Linked Proteins; D005818:Genetic Engineering; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D019169:Jurkat Cells; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D011948:Receptors, Antigen, T-Cell