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Arming Tumor-Reactive T Cells with Costimulator B7-1 Enhances Therapeutic Efficacy of the T Cells

¹ Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, Illinois; ² Department of Histology and Embryology, Second Military Medical University, Shanghai, China; and ³ Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Aoshuang Chen or Guoxing Zheng, Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, 1601 Parkview Avenue, Rockford, IL 61107. Phone: 815-395-5680; Fax: 815-395-5666; E-mail: aoshuang{at}uic.edu or guoxingz{at}uic.edu.

T cells ectopically expressing costimulators are pathogenic and contribute to autoimmunity against self-antigens. Given that tumor antigens are often self-antigen or mutated self-antigens, we hypothesize that neoexpressing a costimulator on tumor-reactive T cells may likewise enhance their reactivity to tumor. To test this hypothesis, we have expressed B7-1 on OT-1 CD8⁺ T-cell receptor transgenic T cells via protein transfer (or protein "painting"). Naïve OT-1 T cells, after being painted with B7-1, can self-costimulate themselves, elicit enhanced proliferative and CTL responses to E.G7-ovalbumin tumor cells (expressing a cognate antigen), and become resistant to CD4⁺CD25⁺ regulatory T-cell-mediated suppression. Importantly, these T cells, when coimplanted with E.G7-ovalbumin tumor cells into a syngeneic host, are three to nine times more potent than are control T cells (mock painted with human IgG) in inhibiting tumor growth. Further, on transfer into mice bearing established E.G7-ovalbumin tumors, B7-1-painted ex vivo–amplified OT-1 T cells induced complete tumor regression in 65% of treated mice, whereas the control T cells did so in only 28% of treated mice. Finally, on transfer into mice bearing less immunogenic 4T1 breast tumors, B7-1-painted tumor-reactive CD8⁺ T cells improved the survival of treated mice to a greater extent than did the control T cells. Hence, this study establishes that arming tumor-reactive T cells with a costimulator can enhance their antitumor efficacy. (Cancer Res 2006; 66(13): 6793-9)

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