Cytokine Gene-Modified Cell-Based Cancer Vaccines

  • R. Todd Reilly
  • Jean-Pascal H. Machiels
  • Leisha A. Emens
  • Elizabeth M. Jaffee
Part of the Methods in Molecular Medicine book series (MIMM, volume 69)


Antitumor immunity was first suggested in animals that reject tumor challenge after immunization with autologous inactivated tumor cells. Later, the discovery of tumor antigens recognized by T-cells strongly reinforced the concept that the tumor can be targeted by the immune system. In 1991, Boon and colleagues described the first human tumor antigen, MAGE-1, that is expressed in 50–60% of melanomas (1). The identification of T-cell-dependent tumor antigens (MAGE family, BAGE, GAGE, HER2/neu, p53, MART-1, tyrosinase, HPV, and others) has opened the route of antigen-specific immunotherapy strategies (2,3). Despite these important advances in tumor immunology, most tumor antigens are still unknown. Until more common tumor-specific antigens have been identified and their prevalence and relevance have been evaluated, the tumor cell itself remains one of the most convenient sources of antigens. Preclinical studies have shown that immunization with modified inactivated tumor cells can generate systemic antitumor immunity in vivo (4). Currently, many clinical studies are investigating the safety and efficacy of autologous and allogeneic whole cell-based cancer vaccines (5).


Tumor Antigen Antitumor Immune Response Transduction Efficiency Vaccine Cell Autologous Tumor Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    van der Bruggen P., Traversari C., Chomez P., et al. (1991) A gene encoding an antigen recognized cytotoxic T lymphocytes on a human melanoma. Science 254, 1643–1648PubMedCrossRefGoogle Scholar
  2. 2.
    Van den Eynde B. J. and van der Bruggen P. (1997) T-cell defined tumor antigens. Curr. Opin. Immunol. 9, 684–693.PubMedCrossRefGoogle Scholar
  3. 3.
    Rosenberg S. A. (1999) A new era for cancer immunotherapy based on the genes that encode cancer antigens. Immunity 10, 281–287.PubMedCrossRefGoogle Scholar
  4. 4.
    Dranoff G., Jaffee E. M., Lazenby A., et al. (1993) Vaccination with irradiated tumor cells engineered to secrete murine GM-CSF stimulates potent, specific, long lasting anti-tumor immunity. Proc. Natl. Acad. Sci. USA 90, 3539–3543.PubMedCrossRefGoogle Scholar
  5. 5.
    Human gene marker/Therapy clinical trial protocols. (1999) Hum. Gene Ther. 10, 1043–1092.CrossRefGoogle Scholar
  6. 6.
    Kruisbeek A. M. and Amsen D. (1996) Mechanisms underlying T-cell tolerance. Curr. Opin. Immunol. 8, 815–821.CrossRefGoogle Scholar
  7. 7.
    Sotomayor E. M., Borrello I., and Levistky H. (1996) Tolerance and cancer. Crit. Rev. Oncog. 7, 433–456.PubMedGoogle Scholar
  8. 8.
    Lipton A., Harvey H. A., Balch C. M., et al. (1991) Corynebacterium parvum versus bacille Calmette-Guérin adjuvant immunotherapy of stage II malignant melanoma. J. Clin. Oncol. 9, 1151–1156.PubMedGoogle Scholar
  9. 9.
    Schirrmacher V., Ahlert T., Probstle T., et al. (1998) Immunization with virus-modified tumor cells. Semin. Oncol. 25, 677–696.PubMedGoogle Scholar
  10. 10.
    Wallich R., Bulbuc N., Hammerling G., et al. (1985) Abrogation of metastatic properties of tumor cells by de novo expression of H-2K antigens following H-2 gene transfection. Nature 315, 301–305.PubMedCrossRefGoogle Scholar
  11. 11.
    Pulaski B. A. and Ostrand-Rosenberg S. (1998) Reduction of established spontaneous mammary carcinoma metastases following immunotherapy with major histocompatibility complex class II and B7.1 cell-based tumor vaccines. Cancer Res. 58, 1486–1493.PubMedGoogle Scholar
  12. 12.
    Chen C. A. and Okayama H. (1988) Calcium phosphate-mediated gene transfer: a highly efficient transfection system for stably transforming cells with plasmid DNA. Biotechniques 6, 882–886.Google Scholar
  13. 13.
    Gordon J. W. (1990) Micromanipulation of embryos and germs cells: an approach to gene therapy? Am. J. Med. Genet. 35, 206–214.PubMedCrossRefGoogle Scholar
  14. 14.
    Kubiniec R. T., Liang H., and Hui S. W. (1990) effects of pulse length and pulse strength on transfection by electroporation. Biotechniques 8, 16–20.PubMedGoogle Scholar
  15. 15.
    Hug P. and Sleight R. G. (1991) Liposomes for the transformation of eukaryotic cells. Biochim. Biophys. Acta 1097, 1–17.PubMedGoogle Scholar
  16. 16.
    Wolff J. A., Malone R. W., Williams P., et al. (1990) Direct gene transfer into mouse muscle in vivo. Science 247, 1465–1468.PubMedCrossRefGoogle Scholar
  17. 17.
    Wu G. Y., Zhan P., Sze L. L., Rosenberg A. R., and Wu C. H. (1994) Incorporation of adenovirus into a ligand-based DNA carrier system results in retention of original receptor specificity and enhances targeted gene expression. J. Biol. Chem. 269, 11542–11546PubMedGoogle Scholar
  18. 18.
    Jiao S., Cheng L., Wolff J. A., and Yang N.-S. (1993) Particle bombardment-mediated gene transfer and expression in rat brain tissues. Biotechnology 11, 497–502.PubMedCrossRefGoogle Scholar
  19. 19.
    Mulligan R. C. (1991) Gene transfer and gene therapy. Principles, prospects, and perspective, in Etiology of Human Diseases at the DNA Level (Lindsten J. and Pettersson U., eds.), Raven, New York, pp. 143–181.Google Scholar
  20. 20.
    Danos O. and Mulligan R. C. (1988) Safe and efficient generation of recombi-nant retroviruses with amphotropic and ecotropic host ranges. Proc. Natl. Acad. Sci. USA 85, 6460–6464.PubMedCrossRefGoogle Scholar
  21. 21.
    Armentano D., Sheau-Fung Y., Kantoff P., et al. (1987) Effect of internal viral sequences on the utility of retroviral vectors. J. Virol. 61, 1647–1650.PubMedGoogle Scholar
  22. 22.
    Jaffee E. M., Dranoff G., Cohen L. W., et al. (1993) High efficiency gene transfer into primary human tumor explants without cell selection. Cancer Res. 53, 2221–2226.PubMedGoogle Scholar
  23. 23.
    Kashara N., Dozy A. M., and Kan Y. W. (1994) Tissue-specific targeting of retroviral vectors through ligand-receptor interactions. Science 266, 1373–1376.CrossRefGoogle Scholar
  24. 24.
    Naldini L., Blomer U., Gallay P., et al. (1996) In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267.PubMedCrossRefGoogle Scholar
  25. 25.
    Quantin B., Perricaudet L. D., Tajbakhsh S., and Mandel J. L. (1992) Adenovi-rus as an expression vector in muscle cells in vivo. Proc. Natl. Acad. Sci. USA 89, 2581–2584.PubMedCrossRefGoogle Scholar
  26. 26.
    Bowman L., Grossmann M., Rill D., et al. (1998) Il-2 adenovector-transduced autologous tumor cells induce antitumor immune responses in patients with neu-roblastoma. Blood 92, 1941–1949.PubMedGoogle Scholar
  27. 27.
    Barth R. J. Jr. and Mule J. J. (1996) Cytokine gene transfer into tumor cells: animal models, in Gene Therapy in Cancer (Brenner M. K. and Moen R. C., eds.), Marcel Dekker, New York, pp. 73–94.Google Scholar
  28. 28.
    Fearon E. R., Pardoll D. M., Itaya T., et al. (1990) Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell 60, 397–403.PubMedCrossRefGoogle Scholar
  29. 29.
    Golumbek P. T., Lazenby A. J., Levitsky H. I., et al. (1991). Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4. Science 254, 713–716.PubMedCrossRefGoogle Scholar
  30. 30.
    Gansbacher B., Zier K., Daniels B., Cronin K., Bannerji R., and Gilboa E. (1990) Interleukin 2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J. Exp. Med. 172, 1217–1224.PubMedCrossRefGoogle Scholar
  31. 31.
    Tepper R. I, Pattengale P. K., and Leder P. (1989) Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell 57, 503–512.PubMedCrossRefGoogle Scholar
  32. 32.
    Hock H., Dorsch M., Diamantstein T., and Blankenstein T. (1991) Interleukin-7 induces CD4+ T-cell dependent tumor rejection. J. Exp. Med. 174, 1291–1298.PubMedCrossRefGoogle Scholar
  33. 33.
    Asher A. L., Mule J. J, Kasid A., et al. (1991) Murine tumor cells transduced with the gene for tumor-necrosis factor-alpha. J. Immunol. 146, 3227–3234.PubMedGoogle Scholar
  34. 34.
    Porgador A., Tzehoval E., Katz A., et al. (1992) Interleukin-6 gene transfection into lewis lung carcinoma tumor cells suppresses the malignant phenotype and confers immunotherapeutic competence against parental metastatic cells. Cancer Res. 52, 3679–3686.PubMedGoogle Scholar
  35. 35.
    Colombo M. P., Ferrari G., Stoppacciaro A., et al. (1991) Granulocyte colony-stimulating factor gene transfer suppresses tumorigenicity of a murine adenocar-cinoma in vivo. J. Exp. Med. 173, 889–897.PubMedCrossRefGoogle Scholar
  36. 36.
    Gansbacher B., Bannerji R., Daniels B., et al. (1990) Retroviral vector-mediated gamma-interferon gene transfer into tumor cells generates potent and long lasting antitumor immunity. Cancer Res. 50, 7820–7825.PubMedGoogle Scholar
  37. 37.
    Hung K., Hayashi R., Lafond-Walker A., et al. (1998) The central role of CD4(+) T-cells in the antitumor immune response. J. Exp. Med. 188, 2357–2368.PubMedCrossRefGoogle Scholar
  38. 38.
    Inaba K., Inaba M., Romani N., et al. (1992) Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 176, 1693–1702.PubMedCrossRefGoogle Scholar
  39. 39.
    Hallez S., Detremmerie O., Giannouli C., et al. (1999) Interleukin-12-secreting human papillomavirus type 16-transformed cells provide a potent cancer vaccine that generates E7-directed immunity. Int. J. Cancer 81, 428–437.PubMedCrossRefGoogle Scholar
  40. 40.
    Tepper R. I. and Mule J. J. (1994) Experimental and clinical studies of cytokine gene-modified tumor cells. Hum. Gene Ther. 5, 153–164.PubMedCrossRefGoogle Scholar
  41. 41.
    Zitvogel L., Robbins P. D., Storkus W. J., et al. (1996) Interleukin-12 and B7.1 co-stimulation cooperate in the induction of effective antitumor immunity and therapy of established tumors. Eur. J. Immunol. 26, 1335–1341.PubMedCrossRefGoogle Scholar
  42. 42.
    Schreiber S., Kampgen E., Wagner E., et al. (1999) Immunotherapy of meta-static malignant melanoma by a vaccine consisting of autologous interleukin 2-transfected cancer cells: outcome of a phase I study. Hum. Gene Ther. 10, 983–993.PubMedCrossRefGoogle Scholar
  43. 43.
    Abdel-Wahab Z., Weltz C., Hester D., et al. (1997) A phase I clinical trial of immunotherapy with interferon-γ gene-modified autologous melanoma cells: monitoring the humoral response. Cancer 80, 401–412.PubMedCrossRefGoogle Scholar
  44. 44.
    Soiffer R., Lynch T., Mihm M., et al. (1998) Vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte-macrophage colony-stimulating factor generates potent antitumor immunity in patients with metastatic melanoma. Proc. Natl. Acad. Sci. USA 95, 13141–13146.PubMedCrossRefGoogle Scholar
  45. 45.
    Simons J. W., Jaffee E. M., Weber C. E., et al. (1997) Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer. Cancer Res. 57, 1537–1546.PubMedGoogle Scholar
  46. 46.
    Moller P., Sun Y., Dorbic T., et al. (1998) Vaccination with Il-7 gene-modified autologous melanoma cells can enhance the anti-melanoma lytic activity in peripheral blood of patients with a good clinical performance status: a clinical phase I study. Br. J. Cancer 77, 1907–1916.PubMedCrossRefGoogle Scholar
  47. 47.
    Sun Y., Jurgovsky K., Moller P., et al. (1998) Vaccination with Il-12 gene-modified autologous melanoma cells: preclinical results and a first clinical phase I study. Gene Ther. 5, 481–490.PubMedCrossRefGoogle Scholar
  48. 48.
    Palmer K., Moore J., Everard M, et al. (1999). Gene therapy with autologous, interleukin-2 secreting tumor cells in patients with malignant melanoma. Hum. Gene Ther. 10, 1261–1268.PubMedCrossRefGoogle Scholar
  49. 49.
    Bernhard H., Karbach J., Wolfel T., et al. (1994) Cellular immune response to human renal-cell carcinomas: definition of a common antigen recognized by HLA-A2-restricted cytotoxic T-lymphocyte (CTL) clones. Int. J. Cancer 59, 837–842.PubMedCrossRefGoogle Scholar
  50. 50.
    Kawakami Y., Eliyahu S., Delgado C. H., et al. (1994) Cloning of the gene coding for a shared human melanoma antigen recognized by autologous T-cells infiltrating into tumor. Proc. Natl. Acad. Sci. USA 91, 3515–3519.PubMedCrossRefGoogle Scholar
  51. 51.
    Huang A. Y. C., Golumbek P., Ahmadzadeh M., et al. (1994) Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 264, 961–965.PubMedCrossRefGoogle Scholar
  52. 52.
    Thomas M. C., Greten T. F., Pardoll D. M, and Jaffee E. M. (1998) Enhanced tumor protection by granulocyte-macrophage colony-stimulating factor expression at the site of an allogeneic vaccine. Hum. Gene Ther. 9, 835–843.PubMedCrossRefGoogle Scholar
  53. 53.
    Arienti F., Sule-Suso J., Belli F., et al. (1996) Limited antitumor T-cell response in melanoma patients vaccinated with interleukin-2 gene-transduced allogeneic melanoma cells. Hum. Gene Ther. 7, 1955–1963.PubMedCrossRefGoogle Scholar
  54. 54.
    Belli F., Arienti F., Sule-Suso J., et al. (1997) Active immunization of meta-static melanoma patients with interleukin-2-transduced allogeneic melanoma cells: evaluation of efficacy and tolerability. Cancer Immunol. Immunother. 44, 197–203.PubMedCrossRefGoogle Scholar
  55. 55.
    Bowman L. C., Grossmann M., Rill D., et al. (1998) Interleukin-2 gene-modified allogeneic tumor cells for treatment of relapsed neuroblastoma. Hum. Gene Ther. 10, 1303–1311.CrossRefGoogle Scholar
  56. 56.
    Jaffee E. M., Abrams R., Cameron J., et al. (1998) A phase I clinical trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene for the treatment of pancreatic adenocarcinoma. Hum. Gene Ther. 9, 1951–1971.PubMedCrossRefGoogle Scholar
  57. 57.
    Veelken H., Mackensen A., Lahn M., et al. (1997) A phase-I clinical study of autologous tumor cells plus interleukin-2-gene-transfected allogeneic fibroblasts as a vaccine in patients with cancer. Int. J. Cancer 70, 269–277PubMedCrossRefGoogle Scholar
  58. 58.
    Mackensen A., Veelken H., Lahn M., et al. (1997) Induction of tumor-specific cytotoxic T lymphocytes by immunization with autologous tumor cells and interleukin-2 gene transfected fibroblasts. J. Mol. Med. 75, 290–296PubMedCrossRefGoogle Scholar
  59. 59.
    Kotani H., Newton P. B., Zhang S., et al. (1994) Improved methods of retroviral vector transduction and production for gene therapy. Hum. Gene Ther. 5, 19–28.PubMedCrossRefGoogle Scholar
  60. 60.
    Cornetta K. and Anderson F. (1989) Protamine sulfate as an effective alternative to Polybrene in retroviral-mediated gene transfer. J. Virol. Methods 23, 187–194.PubMedCrossRefGoogle Scholar
  61. 61.
    Leventis R. and Silvius J. R. (1990) Interactions of mammalian cells with lipid dispersions containing novel metabolizable cationic amphiphiles. Biochem. Biophys. Acta 1023, 124–132.PubMedCrossRefGoogle Scholar
  62. 62.
    Gearing A. J. H. and Bird C. B. (1987) Production and assay of Il-2, in Lymphok-ines and Interferons, a Practical Approach (Clemens M. J., Morris A. G., and Gearing A. J. H, eds.), IRL, Washington, DC, pp. 291–301.Google Scholar
  63. 63.
    Coligan J. E., Kruisbeck A. M., Margulies D. H., Shevach E. M., and Strober W. (1991) Current Protocols in Immunology, Greene and Wiley-Interscience, New York.Google Scholar
  64. 64.
    Kitanura T., Tojo A., Kuwaki T., et al. (1989) Identification and analysis of human erythropoietin receptors on a factor-dependent cell line, TF-1. Blood 73, 375–380.Google Scholar
  65. 65.
    Holmes K. L., Palaszymski E., and Fredrikson T. (1985) Correlation of cell-surface phenotype with the establishment of interleukin3-dependent cell lines from wild-mouse murine leukemia with virus-induced neoplasms. Proc. Natl. Acad. Sci. USA 82, 6687–6691.PubMedCrossRefGoogle Scholar
  66. 66.
    Yokota T., Otsuka T., Mosmann T., et al. (1986) Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B cell stimulatory factor 1, that expresses B cell stimulatory factor 1, that expresses B cell-and T-cell-stimulating activities. Proc. Natl. Acad. Sci. USA 83, 5894–5898.PubMedCrossRefGoogle Scholar
  67. 67.
    Nordan R. P., Pumphrey J. G., and Rudikoff S. (1987) Purification and NH2-terminal sequence of a plasmocytoma growth factor derived from the murine mac-rophage cell line P388D1. J. Immunol. 193, 813–817.Google Scholar
  68. 68.
    Jaffee E. M., Thomas M. C., Huang A. Y., et al. (1996) Enhanced immune priming with spatial distribution of paracrine cytokine vaccines. J. Immunother. Emphasis Tumor Immunol. 19, 176–183.PubMedCrossRefGoogle Scholar
  69. 69.
    Jaffee E. M., Schutte M., Gossett J., et al. (1998) Development and characterization of a cytokine-secreting pancreatic adenocarcinoma vaccine from primary tumors for use in clinical trials. Cancer J. Sci. Am. 4, 194–203.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2002

Authors and Affiliations

  • R. Todd Reilly
    • 1
  • Jean-Pascal H. Machiels
    • 2
  • Leisha A. Emens
    • 3
  • Elizabeth M. Jaffee
    • 3
  1. 1.Department of OncologyBrown UniversityBaltimore
  2. 2.Laboratoire d’Oncologie ExperimentaleUniversitè Catholique de LouvainRusselsBelgium
  3. 3.Department of OncologyThe John Hopkins University School of MedicineBaltimore

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