© 1993 by Oxford University Press
Journal of the National Cancer Institute, Vol. 85, No. 3, 207-216,
February 3, 1993
© 1993 Oxford University Press
Human Renal Carcinoma Line Transfected With Interleukin-2 and/or Interferon 
Gene(s): Implications for Live Cancer Vaccines
Immunotherapy Laboratory, Division of Urology, Department of Surgery, The Jonsson Comprehensive Cancer Center, UCLA School of Medicine Los Angeles, Calif
Department of Radiation Oncology, The Jonsson Comprehensive Cancer Center, UCLA School of Medicine Los Angeles, Calif
Department of Pathology, The Jonsson Comprehensive Cancer Center, UCLA School of Medicine Los Angeles, Calif
Tissue Typing Laboratory, UCLA School of Medicine
Department of Oncology, Hoffmann-La Roche Inc. Nutley, N.J.
Correspondence to: Dr. Arie Belldegrun, Division of Urology, Department of Surgery, UCLA School of Medicine, Los Angeles, CA 90024.
Background: Combination therapy with systemically administered interleukin-2 (IL-2) and interferon 
(IFN-) has resulted in long-term objective remissions in 30% of patients with metastatic renal cell carcinoma (RCC), but toxic effects are clinically significant. Purpose: We have thus investigated an alternative therapeutic approach—continuous intratumoral production of IL-2 and/or IFN- by a cytokine-transfected human RCC tumor cell line. Methods: Plasmid vectors were used to transfect the R11 RCC line with the genes for human IL-2 and/or IFN- by the calcium phosphate precipitation method. Biologic characteristics of the cytokine-transfected tumor cells were determined by assays of thymidine incorporation and cytotoxicity, fluorescence-activated cell-sorter analysis, Northern blotting, and in vivo studies in C3Hf/Sed/Kam mice rendered T-cell deficient. Results: The transfected cell lines produced the following amounts of cytokine per 106 cells per day: R11-IL-2 (220 U), R11-IFN- (10240 U), and R11-IL-2 + IFN- (95-U + 1270 U, respectively). Gamma irradiation did not eliminate cytokine secretion. Morphology and growth rates were identical to those for the parental R11 cell line, except for IFN--producing clones, which showed significant growth inhibition. All cytokine-producing cells demonstrated increased susceptibility to cell killing by peripheral blood leukocytes (PBL). IFN- producers exhibited enhanced HLA antigen expression and suppressed c-myc messenger RNA expression; when cocultured in vitro, they induced similar changes in parental R11 cells. IL-2 producers could stimulate growth and cytotoxicity of naive (i.e., freshly isolated, uncultured) and activated PBL. All cytokine-producing cells lost their tumorigenicity, as evidenced by failure to grow in the T-cell-depleted mice. When co-injected at a local site but not at a distant site, these cells prevented growth of parental R11 cells. Histologic examination of the injection sites revealed a substantial influx of macrophages. Intraperitoneal administration of IL-2 and/or IFN- could not, however, prevent growth of the parental R11 tumors. Conclusion: Local production of high concentrations of IL-2 and IFN- at the tumor site is more effective in preventing tumor growth than systemic administration. Implication: Continuous local delivery of cytokines via transfer of cytokine genes into tumor cells for use as live cancer vaccines is a novel strategy for manipulation of host-mediated antitumor immune response in patients with advanced RCC. [J Natl Cancer Inst 85:207–216, 1993]
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