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

• Published in: Neoplasia (New York, N.Y.) Vol. 1; no. 2; pp. 123 - 127
• Main Authors: Gong, Michael C., Latouche, Jean-Baptiste, Krause, Anja, Heston, Warren D.W., Bander, Neil H., Sadelain, Michel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.1999; Stockton Press; Elsevier
• Subjects: 3T3 Cells; Aged; Aged, 80 and over; Animals; Antigens, Surface; Carboxypeptidases - metabolism; CD28 Antigens - metabolism; Cell Separation; Coculture Techniques; costimulation; Cytokines - biosynthesis; Epithelial Cells - metabolism; Fibroblasts - metabolism; Flow Cytometry; gene therapy; Gene Transfer Techniques; Glutamate Carboxypeptidase II; Humans; immunotherapy; Male; Mice; Middle Aged; prostate cancer; Prostatic Neoplasms - immunology; Prostatic Neoplasms - metabolism; Recombinant Fusion Proteins - metabolism; retroviral-mediated gene transfer; Retroviridae - metabolism; Signal Transduction; T-Lymphocytes - metabolism; T-Lymphocytes, Cytotoxic - immunology; TCR; Pz-1; gene therapy; MHC; IL-2; NTP; IFN; prostate cancer; FITC; PSMA; costimulation; PE; scFv; immunotherapy; retroviral-mediated gene transfer; CTL; PBL
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1038/sj.neo.7900018

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 ζ 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.