HUMAN RENAL-CARCINOMA LINE TRANSFECTED WITH INTERLEUKIN-2 AND OR INTERFERON-ALPHA GENE(S) - IMPLICATIONS FOR LIVE CANCER VACCINES

被引:97
作者
BELLDEGRUN, A
TSO, CL
SAKATA, T
DUCKETT, T
BRUNDA, MJ
BARSKY, SH
CHAI, J
KABOO, R
LAVEY, RS
MCBRIDE, WH
DEKERNION, JB
机构
[1] UNIV CALIF LOS ANGELES, SCH MED, JONSSON COMPREHENS CANC CTR, DEPT PATHOL, LOS ANGELES, CA USA
[2] UNIV CALIF LOS ANGELES, SCH MED, JONSSON COMPREHENS CANC CTR, DEPT RADIAT ONCOL, LOS ANGELES, CA USA
[3] HOFFMANN LA ROCHE INC, DEPT ONCOL, NUTLEY, NJ 07110 USA
[4] UNIV CALIF LOS ANGELES, SCH MED, TISSUE TYPING LAB, LOS ANGELES, CA USA
关键词
D O I
10.1093/jnci/85.3.207
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Combination therapy with systemically administered interleukin-2 (IL-2) and interferon alpha (IFN-alpha) 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-alpha 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-alpha 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-alpha (10240 U), and R11-IL-2 + IFN-alpha (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-alpha-producing clones, which showed significant growth inhibition. All cytokine-producing cells demonstrated increased susceptibility to cell killing by peripheral blood leukocytes (PBL). IFN-alpha 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-alpha could not, however, prevent growth of the parental Rll tumors. Conclusion: Local production of high concentrations of IL-2 and IFN-alpha 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.
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页码:207 / 216
页数:10
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