Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen.
The expression of immunoglobulin-based artificial receptors in normal T lymphocytes provides a means to target lymphocytes to cell surface antigens independently of major histocompatibility complex restriction. Such artificial receptors have been previously shown to confer antigen-specific tumoricidal properties in murine T cells. We constructed a novel zeta chain fusion receptor specific for prostate-specific membrane antigen (PSMA) termed Pz-1. PSMA is a cell-surface glycoprotein expressed on prostate cancer cells and the neovascular endothelium of multiple carcinomas. We show that primary T cells harvested from five of five patients with different stages of prostate cancer and transduced with the Pz-1 receptor readily lyse prostate cancer cells. Having established a culture system using fibroblasts that express PSMA, we next show that T cells expressing the Pz-1 receptor release cytokines in response to cell-bound PSMA. Furthermore, we show that the cytokine release is greatly augmented by B7.1-mediated costimulation. Thus, our findings support the feasibility of adoptive cell therapy by using genetically engineered T cells in prostate cancer patients and suggest that both CD4+ and CD8+ T lymphocyte functions can be synergistically targeted against tumor cells.
Department of Human Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
M C
MC
Gong
J B
JB
Latouche
A
A
Krause
W D
WD
Heston
N H
NH
Bander
M
M
Sadelain
D016475:3T3 Cells; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000954:Antigens, Surface; D018106:CD28 Antigens / Q000378:metabolism; D002268:Carboxypeptidases / Q000378:metabolism*; D002469:Cell Separation; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D043425:Glutamate Carboxypeptidase II; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000954:Antigens, Surface; D018106:CD28 Antigens; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II