Development of Dendritic Cell-Based Genetic Vaccines for Cancer

  • T. Tüting
  • T. Zorina
  • D. I. Ma
  • C. C. Wilson
  • C. M. De Cesare
  • A. B. De Leo
  • M. T. Lotze
  • W. J. Storkus
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 417)


Cytotoxic T lymphocytes (CTL) are an important component of the host’s immune response to cancer1,2. A number of genes encoding tumor-associated antigens (TAA) and their peptide products which are recognized by CTL in the context of major histocompatibility complex (MHC) class I molecules have recently been identified3,4. Our group has focused on the translation of these new insights into the development and application of novel immunotherapies.


Dendritic Cell Human Papilloma Virus Antitumor Immunity Pittsburgh Cancer Institute Protective Antitumor Immunity 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kast, W. M. et al. Eradication of adenovirus E 1-induced tumors by E1 A-specific cytotoxic T lymphocytes. Cell 59, 603–607 (1989)Google Scholar
  2. 2.
    Rosenberg, S.A. et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma: preliminary report. N. Engl. J. Med. 319, 1676–1680 (1988).PubMedCrossRefGoogle Scholar
  3. 3.
    Van den Eynde, B., and Brichard, V.G. New tumor antigens recognized by T cells. Current Opinion in Immunology 7, 674–68 (1995).PubMedCrossRefGoogle Scholar
  4. 4.
    Boon, T., and Van der Bruggen, P. Human tumor Antigens recognized by T lymphocytes. J. Exp. Med. 183, 725–729 (1996).PubMedCrossRefGoogle Scholar
  5. 5.
    Steinman, R.M. The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol. 9, 271–296 (1991).PubMedCrossRefGoogle Scholar
  6. 6.
    Sting!, G., and Bergstresser, P. R. Dendritic cells: a major story unfolds. Immunol. Today 16, 330–333 (1995).CrossRefGoogle Scholar
  7. 7.
    Inaba, K., Steinman, R.M., Witmer-Pack, M., Aya, H., Inaba, M., Sudo, T., Wolpe, S., and Schuler, G. Identification of proliferating dendritic cell precursors in mouse blood. J. Exp. Med. 175, 157–1167 (1992).CrossRefGoogle Scholar
  8. 8.
    Inaba, K., Inaba, M., Romani. N., Aya, H., Deguchi, M., Ikehara, S., Muramatsu. S.. and Steinman, R.M. Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte-macrophage colony-stimulating factor. J. Exp. Med. 176, 693–1702 (1992).CrossRefGoogle Scholar
  9. 9.
    Caux, C., Dezutter-Damboyant, C., Schmitt, D., and Bancherau, J. GM-CSF and TNF-alpha cooperate in the generation of dendritic Langerhans cells. Nature 360, 258–261 (1992).PubMedCrossRefGoogle Scholar
  10. 10.
    Romani, N., Gruner, S., Brang, D., Kämpgen, E., Lenz, A., Trockenbacher, B., Konwalinka, G., Gritsch, P.O., Steinman, R.M. and Schuler. Proliferating dendritic cell progenitors in human blood. J. Exp. Med. 180, 83–93 (1994).CrossRefGoogle Scholar
  11. 11.
    Szabolcs, P., Moore, M.A. S., and Young, J.W. Expansion of immunostimulatory dendritic cells among the myeloid progeny of human CD34+ bone marrow precursors cultured with c-kit ligand, granulocyte-macrophage colony-stimulating factor, and TNF-a. J. Immunol. 154, 5851–5861 (1995).PubMedGoogle Scholar
  12. 12.
    Mayordomo, J.I., Zorina, T., Storkus, W.J., Celuzzi, C.M., Falo, L.D., Kast, W.M., lldstad, S.T., DeLeo, A.B., and Lotze, M.T. Bone marrow-derived dendritic cells pulsed with tumor peptides elicit protective and therapeutic anti-tumor immunity. Nature Med. I. 1297–1302 (1995).Google Scholar
  13. 13.
    Ossevoort, M.A, Feltkamp, M.C.W., van Veen, K.J.H., Melief, C.J.M., and Kast, W.M. Dendritic cells as carriers for a cytotoxic T lymphocyte epitope-based peptide vaccine in protection against a human papillomavirus type 16-induced tumor. J. Immunother. 18, 86–94 (1995).CrossRefGoogle Scholar
  14. 14.
    Celluzi, C.M., Mayordomo, J.I., Storkus, W.J., Lotze, M.T., and Falo, L.D. Peptide-pulsed dendritic cells induce antigen-specific, CTL-mediated protective tumor immunity. J. Exp. Med. 183, 283–387 (1996).CrossRefGoogle Scholar
  15. 15.
    Paglia, P., Chiodoni, C., Rodolfo, M., and Colombo, M.P. Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J. Exp. Med. 183. 317–322 (1996).CrossRefGoogle Scholar
  16. 16.
    Zitvogel, L., Mayordomo, J.I., Tjandrawan, T., DeLeo, A.B., Clarke, M.R., Lotze, M.T., and Storkus, W.J. Therapy of murine tumors with tumor peptide pulsed dendritic cells: dependence on T cells, B7 costimulation, and Th I -associated cytokines. J. Exp. Med. 183. 87–97 (1996).PubMedCrossRefGoogle Scholar
  17. 17.
    Mayordomo, J.I., Loftus, D.J., Sakamoto, H., De Cesare, S.M., Appasamy, P. M., Lotze, M.T., Storkus, W.J., Appella, E., and DeLeo, A.B. Therapy of murine tumors with p53 wild-type and mutant sequence peptide-based vaccines. J. Exp. Med. 183, 1357–1365 (1996).PubMedCrossRefGoogle Scholar
  18. 18.
    Porgador, A., Snyder, D., and Gilboa, E. Induction of antitumor immunity using hone marrow-generated dendritic cells. J. (mmunol. 156, 2918–2926 (1996).Google Scholar
  19. 19.
    Bakker, A.B.H., Marland, G., de Boer, A.J., Huijbens, J.F., Danen, E.H.J., Adema, G.J., and Figdor, D.G. Generation of antimelanoma cytotoxic T lymphocytes from healthy donors after presentation of melanoma-associated antigen-derived epitopes by dendritic cells in vitro. Cancer Res. 55, 5330–5334 (1995).Google Scholar
  20. 20.
    van Elsas, A., van der Burg, S.H., van der Minne, C.E., Borghi, M., Mourer, J.S., Melief, C.J.M., and Schrier, P.1. Peptide-pulsed dendritic cells induce tumoricidal cytotoxic T lymphocytes from healthy donors against stably HLA-A*020 1 -binding peptides from the Melan-A/MART-1 self antigen. Eur. J. Immunol. 26, 1683–1689 (1996).Google Scholar
  21. 21.
    Tjandrawan, T., Mäurer, Mchwr(133)1., Castelli, C., Lotze, M.T., and Storkus, W.J. Autologous dendritic cells pulsed with synthetic melanoma peptides elicit specific CTL effector cells in vitro. Manuscript submitted.Google Scholar
  22. 22.
    Conry, R.M., LoBuglio, Locchel, F., Moore, S.E., Sumerel, L.A., Barlow, D.L., and Curie], D.T. A cardnoembryonic antigen polynucleotide vaccine has in vivo antitumor activity. Gene Ther. 2, 59–66 66 (1995).Google Scholar
  23. 23.
    D.M., and Wu, T.-C. Treatment of established tumors with a novel vaccine that enhances major histocompatibility class II presentation of tumor antigen. Cancer Res. 56,21–26 (1996).Google Scholar
  24. 24.
    Ciernik,LF., Berzofsky, J.A., and Carbone, D. Induction of cytotoxic T lymphocytes and antitumor immunity with DNA vaccines expressing single T cell epitopes. J. Immunol. 156, 2369–2375 (1996).Google Scholar
  25. 25.
    Wamier, G., Duffour, M.-T., Uyttenhove, C., Gajewski, T., Lurquin, C., Haddada, H., Perricaudet, M., and Boon, T. Induction of a cytolytic T-cell response in mice with a recombinant adenovirus coding for tumor antigen P815A. Int. J. Cancer 67, 303–310 (1996).Google Scholar
  26. 26.
    Chen, P.W., Wang, M., Bronte, V., Zhai, Y., Rosenberg, S.A., and Restifo, N.P. Therapeutic antitumor response after immunization with a recombinant adenovirus encoding a model tumor-associated antigen. J. Immunol. 156, 224–231 (1996).PubMedGoogle Scholar
  27. 27.
    Irvine, K.R., Rao, R.B., Rosenberg, S.A., and Restifo, N.P. Cytokine enhancement of DNA immunization leads to effective treatment of established pulmonary metastases. J. Immunol. 156, 238–245 (1996).PubMedGoogle Scholar
  28. 28.
    Zhai, Y., Yang, J.C., Kawakami, Y., Spiess, P., Wadsworth, S.C., Cardoza, L.M., Couture, L.A., Smith, A.E., and Rosenberg, S.A. Antigen-specific tumor vaccines. Development and characterization of recombinant adenoviruses encoding MART I or gp 100 for cancer therapy. J. Immunol. 156, 700–710 (1996).PubMedGoogle Scholar
  29. 29.
    Yang, N.-S., Burkholder, J.K., Roberts, B., Martinell, B., and McCabe, D. In vivo and in vitro gene transfer to mammalian somatic cells by particle bombardment. Proc. Natl. Acad. Sci. USA 87, 9568–9572 (1990).Google Scholar
  30. 30.
    Burkholder, J.K., Decker, J., and Yang, N.-S. Rapid transgene expression in lymphocyte and macrophage primary cultures after particle bombardment-mediated gene transfer. J. Immunol. Methods 165, 149–156 (1993).PubMedCrossRefGoogle Scholar
  31. 31.
    Yang, N.-S., and Sun, W.-H. Gene gun and other non-viral approaches for cancer gene therapy. Nature Med. 1, 481–483 (1995).PubMedCrossRefGoogle Scholar
  32. 32.
    Pertmer, T.M., Roberts, T.R., and Haynes, J.R. Influenza virus nucleoprotein-specific immunoglobulin G subclass and cytokine responses elicited by DNA vaccination are dependent on the route of vector DNA delivery. J.Virol. 76: 6119–6125 (1996).Google Scholar
  33. 33.
    Feltkamp, M.C.W., Smis, H.L., Vierboom, M.P.M., Minnaar, R.P., de Jongh, B.M., Drijfhout, J.W., ter Schegget, J., Melief, C.J.M., and Kast, W.M. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. Eur. J. Immunol. 23, 2242–2249 (1993).Google Scholar
  34. 34.
    Henderson, R.A., Nimgaonkar, M.T., Watkins, S.C., Robbins, P.D., Ball, E.D., and Finn, O.J. Human dendritic cells genetically engineered to express high levels of the human epithelial tumor antigen mucin (MUC-I). Cancer Res. 56, 3763–3770 (1996).PubMedGoogle Scholar
  35. 35.
    Ressing, M.E., Sette, A., Brandt, R.M., Ruppert, J., Wentworth, P.A., Hartmann, M., Oseroff, C., Grey, H.M., Melief, C.J.M., and Kast, W.M. Human CTL epitopes encoded by human papillomavirus type 16 E6 and E7 identified through in vivo and in vitro immunogenicity studies of HLA-A*0201-binding peptides. J. Immunol. 154: 5934–5943 (1995).PubMedGoogle Scholar
  36. 36.
    Houbiers, J.G.A., Nijman, H.W., van der Burg, S.H., Drijfhout, J.W., Kenemans, R, man de Velde, C.J.H., Brand, A., Momburg, F., Kast, W.M., and Melief, C.J.M. In vitro induction of human cytotoxic T lymphocyte responses against peptides of mutant and wild-type p53. Eur. J. Immunol. 23:2072–2077 (1993).Google Scholar
  37. 37.
    Theobald, M., Biggs, J., Dittmer, D., Levine, A., and Sherman, L. Targeting p53 as a general tumor antigen. Proc. Natl. Acad. Sci. USA 92: 11993–11997 (1995).PubMedCrossRefGoogle Scholar
  38. 38.
    Roth, J.A., Nguyen, D., Lawrence, D.D., Kemp, B.L., Carrasco, C.H., Ferson, D.Z,., Hong,W.K., Komari, R., Lee, J.J., Nesbitt, J.C., Pisters, K.M.W., Putnam, J.B., Schea, R., Shin, D.M., Walsh, D.L., Dolormente, M.M., Han, C.-1., Martin, F.D., Yen, N., Xu, K., Stephens, L.C., McDonnell, T.J., Mukhopadhyay, T., and Cai, T. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. Nature Med. 2: 985–991 (1996).Google Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • T. Tüting
    • 1
  • T. Zorina
    • 1
  • D. I. Ma
    • 1
  • C. C. Wilson
    • 1
  • C. M. De Cesare
    • 1
  • A. B. De Leo
    • 1
  • M. T. Lotze
    • 1
  • W. J. Storkus
    • 1
  1. 1.Department of Surgery and the Pittsburgh Cancer InstituteUniversity of PittsburghPittsburghUSA

Personalised recommendations