Anti-prostate specific membrane antigen designer T cells for prostate cancer therapy.
BACKGROUND
Designer T cells are T lymphocytes engineered toward specific antibody-type membrane antigens through chimeric immunoglobulin-T-cell receptor (IgTCR) genes that have been used for adoptive cellular immunotherapy. We have extended this approach to prostate specific membrane antigen (PSMA) as a means to attack prostate cancer.


METHODS
A chimeric anti-PSMA IgTCR gene was constructed based on an anti-PSMA monoclonal antibody, 3D8. Both T-cell lines and primary cultured human T lymphocytes were transduced with the chimeric anti-PSMA IgTCR construct and were analyzed for IgTCR expression, specific activation by PSMA, cytotoxicity against PSMA-expressing tumor cells in vitro, and retardation of tumor growth in an animal model.


RESULTS
The IgTCR was incorporated into the TCR-CD3 complex and formed a functional chimeric complex. The IgTCR-modified T cells were specifically activated through the chimeric receptor with PSMA as measured by IL-2 production and increased CD25 expression and specifically lysed the PSMA-expressing prostate cancer cells in vitro as well as retarded tumor growth in an animal model.


CONCLUSIONS
The anti-PSMA designer T cells exhibit an antibody-type specificity that can recognize PSMA expressing tumor cells in a MHC-independent fashion, resulting in T-cell activation, target cell lysis in vitro and inhibition of tumor growth in vivo.
Ma
Qiangzhong
Q
Biotherapeutics Development Lab, Division of Hematology-Oncology, Beth Israel Deaconess Medical Center and Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Safar
Mazin
M
Holmes
Eric
E
Wang
Yawen
Y
Boynton
Alton L
AL
Junghans
Richard P
RP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology; D000954:Antigens, Surface / Q000276:immunology*; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology*; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011233:Precipitin Tests; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II