Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Apr 1;177(4):1127–1134. doi: 10.1084/jem.177.4.1127

Regression of bladder tumors in mice treated with interleukin 2 gene- modified tumor cells [published erratum appears in J Exp Med 1993 Jun 1;177(6):following 1831]

PMCID: PMC2190983  PMID: 8459207

Abstract

This study explored the use of interleukin 2 (IL-2) and interferon gamma (IFN-gamma) 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- gamma 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-gamma-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-gamma-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-gamma-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.

Full Text

The Full Text of this article is available as a PDF (835.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aoki T., Tashiro K., Miyatake S., Kinashi T., Nakano T., Oda Y., Kikuchi H., Honjo T. Expression of murine interleukin 7 in a murine glioma cell line results in reduced tumorigenicity in vivo. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3850–3854. doi: 10.1073/pnas.89.9.3850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Armentano D., Yu S. F., Kantoff P. W., von Ruden T., Anderson W. F., Gilboa E. Effect of internal viral sequences on the utility of retroviral vectors. J Virol. 1987 May;61(5):1647–1650. doi: 10.1128/jvi.61.5.1647-1650.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Asher A. L., Mulé J. J., Kasid A., Restifo N. P., Salo J. C., Reichert C. M., Jaffe G., Fendly B., Kriegler M., Rosenberg S. A. Murine tumor cells transduced with the gene for tumor necrosis factor-alpha. Evidence for paracrine immune effects of tumor necrosis factor against tumors. J Immunol. 1991 May 1;146(9):3227–3234. [PMC free article] [PubMed] [Google Scholar]
  4. Bubenik J., Voitenok N. N., Kieler J., Prassolov V. S., Chumakov P. M., Bubenikova D., Simova J., Jandlova T. Local administration of cells containing an inserted IL-2 gene and producing IL-2 inhibits growth of human tumours in nu/nu mice. Immunol Lett. 1988 Dec;19(4):279–282. doi: 10.1016/0165-2478(88)90155-1. [DOI] [PubMed] [Google Scholar]
  5. Bubeník J., Perlmann P., Indrová M., Símová J., Jandlová T., Neuwirt J. Growth inhibition of an MC-induced mouse sarcoma by TCGF (IL 2)-containing preparations. Preliminary report. Cancer Immunol Immunother. 1983;14(3):205–206. doi: 10.1007/BF00205362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bubeník J., Símová J., Jandlová T. Immunotherapy of cancer using local administration of lymphoid cells transformed by IL-2 cDNA and constitutively producing IL-2. Immunol Lett. 1990 Feb;23(4):287–292. doi: 10.1016/0165-2478(90)90074-z. [DOI] [PubMed] [Google Scholar]
  7. Cheever M. A., Thompson J. A., Peace D. J., Greenberg P. D. Potential uses of interleukin 2 in cancer therapy. Immunobiology. 1986 Sep;172(3-5):365–382. doi: 10.1016/S0171-2985(86)80118-8. [DOI] [PubMed] [Google Scholar]
  8. Cullen B. R. Expression of a cloned human interleukin-2 cDNA is enhanced by the substitution of a heterologous mRNA leader region. DNA. 1988 Nov;7(9):645–650. doi: 10.1089/dna.1988.7.645. [DOI] [PubMed] [Google Scholar]
  9. Fearon E. R., Pardoll D. M., Itaya T., Golumbek P., Levitsky H. I., Simons J. W., Karasuyama H., Vogelstein B., Frost P. Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell. 1990 Feb 9;60(3):397–403. doi: 10.1016/0092-8674(90)90591-2. [DOI] [PubMed] [Google Scholar]
  10. Fidler I. J. Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture. Cancer Res. 1990 Oct 1;50(19):6130–6138. [PubMed] [Google Scholar]
  11. Forni G., Giovarelli M., Santoni A. Lymphokine-activated tumor inhibition in vivo. I. The local administration of interleukin 2 triggers nonreactive lymphocytes from tumor-bearing mice to inhibit tumor growth. J Immunol. 1985 Feb;134(2):1305–1311. [PubMed] [Google Scholar]
  12. Forni G., Giovarelli M., Santoni A., Modesti A., Forni M. Tumour inhibition by interleukin-2 at the tumour/host interface. Biochim Biophys Acta. 1986 Dec 17;865(3):307–327. doi: 10.1016/0304-419x(86)90020-x. [DOI] [PubMed] [Google Scholar]
  13. Forni G., Musso T., Jemma C., Boraschi D., Tagliabue A., Giovarelli M. Lymphokine-activated tumor inhibition in mice. Ability of a nonapeptide of the human IL-1 beta to recruit anti-tumor reactivity in recipient mice. J Immunol. 1989 Jan 15;142(2):712–718. [PubMed] [Google Scholar]
  14. Gansbacher B., Bannerji R., Daniels B., Zier K., Cronin K., Gilboa E. Retroviral vector-mediated gamma-interferon gene transfer into tumor cells generates potent and long lasting antitumor immunity. Cancer Res. 1990 Dec 15;50(24):7820–7825. [PubMed] [Google Scholar]
  15. Gansbacher B., Zier K., Daniels B., Cronin K., Bannerji R., Gilboa E. Interleukin 2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J Exp Med. 1990 Oct 1;172(4):1217–1224. doi: 10.1084/jem.172.4.1217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Golumbek P. T., Lazenby A. J., Levitsky H. I., Jaffee L. M., Karasuyama H., Baker M., Pardoll D. M. Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4. Science. 1991 Nov 1;254(5032):713–716. doi: 10.1126/science.1948050. [DOI] [PubMed] [Google Scholar]
  17. Hantzopoulos P. A., Sullenger B. A., Ungers G., Gilboa E. Improved gene expression upon transfer of the adenosine deaminase minigene outside the transcriptional unit of a retroviral vector. Proc Natl Acad Sci U S A. 1989 May;86(10):3519–3523. doi: 10.1073/pnas.86.10.3519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hewitt H. B., Blake E. R., Walder A. S. A critique of the evidence for active host defence against cancer, based on personal studies of 27 murine tumours of spontaneous origin. Br J Cancer. 1976 Mar;33(3):241–259. doi: 10.1038/bjc.1976.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kamo I., Friedman H. Immunosuppression and the role of suppressive factors in cancer. Adv Cancer Res. 1977;25:271–321. doi: 10.1016/s0065-230x(08)60636-3. [DOI] [PubMed] [Google Scholar]
  20. Lee R. E., Lotze M. T., Skibber J. M., Tucker E., Bonow R. O., Ognibene F. P., Carrasquillo J. A., Shelhamer J. H., Parrillo J. E., Rosenberg S. A. Cardiorespiratory effects of immunotherapy with interleukin-2. J Clin Oncol. 1989 Jan;7(1):7–20. doi: 10.1200/JCO.1989.7.1.7. [DOI] [PubMed] [Google Scholar]
  21. Ley V., Langlade-Demoyen P., Kourilsky P., Larsson-Sciard E. L. Interleukin 2-dependent activation of tumor-specific cytotoxic T lymphocytes in vivo. Eur J Immunol. 1991 Mar;21(3):851–854. doi: 10.1002/eji.1830210350. [DOI] [PubMed] [Google Scholar]
  22. Markowitz D., Goff S., Bank A. Construction and use of a safe and efficient amphotropic packaging cell line. Virology. 1988 Dec;167(2):400–406. [PubMed] [Google Scholar]
  23. McKnight S. L. The nucleotide sequence and transcript map of the herpes simplex virus thymidine kinase gene. Nucleic Acids Res. 1980 Dec 20;8(24):5949–5964. doi: 10.1093/nar/8.24.5949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. North R. J. Down-regulation of the antitumor immune response. Adv Cancer Res. 1985;45:1–43. doi: 10.1016/s0065-230x(08)60265-1. [DOI] [PubMed] [Google Scholar]
  25. Pizza G., Severini G., Menniti D., De Vinci C., Corrado F. Tumour regression after intralesional injection of interleukin 2 (IL-2) in bladder cancer. Preliminary report. Int J Cancer. 1984 Sep 15;34(3):359–367. doi: 10.1002/ijc.2910340312. [DOI] [PubMed] [Google Scholar]
  26. Porgador A., Bannerji R., Watanabe Y., Feldman M., Gilboa E., Eisenbach L. Antimetastatic vaccination of tumor-bearing mice with two types of IFN-gamma gene-inserted tumor cells. J Immunol. 1993 Feb 15;150(4):1458–1470. [PubMed] [Google Scholar]
  27. Porgador A., Tzehoval E., Katz A., Vadai E., Revel M., Feldman M., Eisenbach L. Interleukin 6 gene transfection into Lewis lung carcinoma tumor cells suppresses the malignant phenotype and confers immunotherapeutic competence against parental metastatic cells. Cancer Res. 1992 Jul 1;52(13):3679–3686. [PubMed] [Google Scholar]
  28. Raghavan D., Shipley W. U., Garnick M. B., Russell P. J., Richie J. P. Biology and management of bladder cancer. N Engl J Med. 1990 Apr 19;322(16):1129–1138. doi: 10.1056/NEJM199004193221607. [DOI] [PubMed] [Google Scholar]
  29. Rosenberg S. A. Immunotherapy of cancer using interleukin 2: current status and future prospects. Immunol Today. 1988 Feb;9(2):58–62. doi: 10.1016/0167-5699(88)91261-3. [DOI] [PubMed] [Google Scholar]
  30. Soloway M. S., Murphy W. M. Experimental chemotherapy of bladder cancer--systemic and intravesical. Semin Oncol. 1979 Jun;6(2):166–183. [PubMed] [Google Scholar]
  31. Wano Y., Cullen B. R., Svetlik P. A., Peffer N. J., Greene W. C. Reconstitution of high affinity IL-2 receptor expression in a human T-cell line using a retroviral cDNA expression vector. Mol Biol Med. 1987 Apr;4(2):95–109. [PubMed] [Google Scholar]
  32. Watanabe Y., Kuribayashi K., Miyatake S., Nishihara K., Nakayama E., Taniyama T., Sakata T. Exogenous expression of mouse interferon gamma cDNA in mouse neuroblastoma C1300 cells results in reduced tumorigenicity by augmented anti-tumor immunity. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9456–9460. doi: 10.1073/pnas.86.23.9456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zier K. S. Functional and antigenic properties of cultured T cells in the cell mediated lympholysis (CML) assay. Hum Immunol. 1982 Apr;4(2):147–156. doi: 10.1016/0198-8859(82)90014-3. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES