Regression of bladder tumors in mice treated with interleukin 2 gene-modified tumor cells

John Connor, Rajat Bannerji, Shiro Saito, Warren Heston, William Fair, Eli Gilboa

Research output: Contribution to journalArticle

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Abstract

This study explored the use of interleukin 2 (IL-2) and Interferon γ (IFN-γ) gene-modified tumor cells as cellular vaccines for the treatment of bladder cancer. The mouse MBT-2 tumor used is an excellent model for human bladder cancer. This carcinogen-induced tumor of bladder origin resembles human bladder cancer in its etiology and histology, and responds to treatment in a manner similar to its human counterpart. Using retroviral vectors, the human IL-2 and mouse IFN-γ genes were introduced and expressed in MBT-2 cells. The tumor-forming capacity of the cytokine gene-modified MBT-2 cells was significantly impaired, since no tumors formed in mice injected intradermally with either IL-2- or IFN-γ-secreting cells, using cell doses far exceeding the minimal tumorigenic dose of parental MBT-2 cells. Furthermore, mice that rejected the IL-2-or IFN-γ-secreting tumor cells became highly resistant to a subsequent challenge with parental MBT-2 cells, but not to 38C13 cells, a B cell lymphoma of the same genetic background. To approximate the conditions as closely as possible to the conditions prevailing in the cancer patient, inactivated cytokine-secreting cells were used to treat animals bearing tumors established by orthotopic implantation of MBT-2 cells into the bladder wall of the animal. Treatment of mice carrying a significant tumor burden with IL-2-secreting MBT-2 cells had a significant inhibitory effect on tumor progression with extended survival. Moreover, in 60% of the mice the tumor regressed completely and the animals remained alive and free of detectable tumor for the duration of the observation period. Treatment of tumor-bearing animals with IL-2-secreting MBT-2 cells was superior to the use of cisplatin, a chemotherapeutic agent used in the treatment of bladder cancer. The therapeutic effect of IFN-γ-secreting cells was minimal and treatment with unmodified MBT-2 cells had no effect on tumor growth or survival, showing that the parental MBT-2 cells were nonimmunogenic in this experimental setting. Most importantly, mice that exhibited complete tumor regression after treatment with IL-2-secreting MBT-2 cells became resistant to a subsequent challenge with a highly tumorigenic dose of parental MBT-2 cells, indicating that long-term immunological memory was established in the "cured" mice.

Original languageEnglish
Pages (from-to)1127-1134
Number of pages8
JournalJournal of Experimental Medicine
Volume177
Issue number4
StatePublished - Apr 1 1993
Externally publishedYes

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Urinary Bladder Neoplasms
Interleukin-2
Genes
Neoplasms
Therapeutics
Immunologic Memory
Cytokines
Survival
Long-Term Memory
B-Cell Lymphoma
Therapeutic Uses
Tumor Burden
Carcinogens
Interferons
Cisplatin

ASJC Scopus subject areas

  • Immunology

Cite this

Regression of bladder tumors in mice treated with interleukin 2 gene-modified tumor cells. / Connor, John; Bannerji, Rajat; Saito, Shiro; Heston, Warren; Fair, William; Gilboa, Eli.

In: Journal of Experimental Medicine, Vol. 177, No. 4, 01.04.1993, p. 1127-1134.

Research output: Contribution to journalArticle

Connor, J, Bannerji, R, Saito, S, Heston, W, Fair, W & Gilboa, E 1993, 'Regression of bladder tumors in mice treated with interleukin 2 gene-modified tumor cells', Journal of Experimental Medicine, vol. 177, no. 4, pp. 1127-1134.
Connor, John ; Bannerji, Rajat ; Saito, Shiro ; Heston, Warren ; Fair, William ; Gilboa, Eli. / Regression of bladder tumors in mice treated with interleukin 2 gene-modified tumor cells. In: Journal of Experimental Medicine. 1993 ; Vol. 177, No. 4. pp. 1127-1134.
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