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Influence of CD80, Interleukin-2, and Interleukin-7 Expression in Human Renal Cell Carcinoma on the Expansion, Function, and Survival of Tumor-Specific CTLs

¹ Institute of Molecular Immunology, Forschungszentrum für Umwelt und Gesundheit-National Research Center for Environment and Health; ² Forschungszentrum für Umwelt und Gesundheit-Clinical Cooperation Group "Urological Tumors," Laboratory for Tumor Immunology, Department of Urology, Ludwig-Maximilians-University, Munich, Germany; ³ Max Delbrück Center for Molecular Medicine; ⁴ Institute of Immunology, Charité-University Medicine Berlin, Campus Benjamin Franklin; ⁵ Department of Hematology, Oncology, and Tumor Immunology, Charité-University Medicine Berlin, Campus Berlin-Buch, Berlin, Germany; and ⁶ Urology Clinic, Munich-Planegg, Germany

Requests for reprints: Bernhard Frankenberger, Institute of Molecular Immunology, Forschungszentrum für Umwelt und Gesundheit-National Research Center for Environment and Health, Marchioninistrasse 25, 81377 Munich, Germany. Phone: 49-89-7099-301; Fax: 49-89-7099-300; E-mail: b.frankenberger{at}gsf.de.

Purpose: A renal cell carcinoma (RCC) line, RCC-26, has been identified as a suitable candidate for development of an allogeneic tumor cell vaccine based on its expression of a variety of tumor-associated antigens (TAA). To improve immunogenicity, RCC-26 cells were genetically engineered to express CD80 alone or in combination with interleukin (IL)-2 or IL-7. The effect of these modifications on proliferation, function, and survival of autologous and allogeneic tumor-specific CTLs was assessed.

Experimental Design: RCC-26 sublines expressing different transgenes were tested for their capacity to reactivate cytokine secretion and cytotoxicity in autologous tumor-infiltrating lymphocytes, to improve proliferation and survival of tumor-associated T cells present in autologous peripheral blood, and to induce tumor-associated responses in naive allogeneic lymphocytes. The expression of several common TAA was quantitated in the RCC-26 sublines using reverse transcription-PCR to identify surrogate markers for immune monitoring in clinical trials.

Results: Gene-modified RCC-26 cells showed enhanced immunogenicity. CD80 expression was necessary to induce RCC-associated CTL in blood of healthy allogeneic donors. It also improved proliferation of autologous effector-memory T cells. Further enhancement was achieved with IL-2 through induction of the antiapoptosis protein Bcl-x_L. The candidate vaccine lines overexpressed several common TAA that are suitable markers for immune monitoring.

Conclusions: RCC-26 cells coexpressing CD80 and cytokine transgenes display improved immunogenic characteristics, supporting their use as allogeneic tumor cell vaccines for HLA-A2-matched patients with metastatic RCC.

Key Words: costimulatory signals • gene therapy • tumor-specific CTL • tumor cell vaccines • renal cell carcinoma

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