Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Cancer immunotherapy: moving beyond current vaccines

Abstract

Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Rosenberg, S.A. Progress in human tumour immunology and immunotherapy. Nature 411, 380–384 (2001).

    Article  CAS  Google Scholar 

  2. Ridgway, D. The first 1000 dendritic cell vaccines. Cancer Invest. 21, 876–886 (2003).

    Article  Google Scholar 

  3. Ribas, A., Butterfield, L.H., Glaspy, J.A. & Economou, J.S. Current developments in cancer vaccines and cellular immunotherapy. J. Clin. Oncol. 21, 2415–2432 (2003).

    Article  CAS  Google Scholar 

  4. Overwijk, W.W. et al. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J. Exp. Med. 198, 569–580 (2003).

    Article  CAS  Google Scholar 

  5. Dudley, M.E. et al. Cancer regression and autoimmunity in patients following clonal repopulation with anti-tumor lymphocytes. Science 298, 850–854 (2002).

    Article  CAS  Google Scholar 

  6. Miller, A.B., Hoogstraten, B., Staquet, M. & Winkler, A. Reporting results of cancer treatment. Cancer 47, 207–214 (1981).

    Article  CAS  Google Scholar 

  7. Therasse, P. et al. New guidelines to evaluate the response to treatment in solid tumors. J. Natl. Cancer. Inst. 92, 205–216 (2000).

    Article  CAS  Google Scholar 

  8. James, K. et al. Measuring response in solid tumors: unidimensional versus bidimensional measurement. J. Natl. Cancer Inst. 91, 523–528 (1999).

    Article  CAS  Google Scholar 

  9. Eberlein, T.J., Rosenstein, M. & Rosenberg, S.A. Successful systemic adoptive immunotherapy of a disseminated solid syngeneic murine tumor with long-term cultured T cells. Transp. Proc. 15, 396–398 (1983).

    Google Scholar 

  10. Hanson, H.L. et al. Eradication of established tumors by CD8+ T cell adoptive immunotherapy. Immunity 13, 265–277 (2000).

    Article  CAS  Google Scholar 

  11. May, K.F., Chen, L., Zheng, P. & Liu, Y. Anti-4-1BB monoclonal antibody enhances rejection of large tumor burden by promoting survival but not clonal expansion of tumor-specific CD8+ T Cells. Cancer Res. 62, 3459–3465 (2002).

    CAS  PubMed  Google Scholar 

  12. Cormier, J.N. et al. Enhancement of cellular immunity in melanoma patients immunized with a peptide from MART-1/Melan A. Cancer J. Sci. Am. 3, 37–44 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Salgaller, M.L., Marincola, F.M., Cormier, J.N. & Rosenberg, S.A. Immunization against epitopes in the human melanoma antigen gp100 following patient immunization with synthetic peptides. Cancer Res. 56, 4749–4757 (1996).

    CAS  PubMed  Google Scholar 

  14. Kammula, S.A., Marincola, F.M. & Rosenberg, S.A. Real-time quantitative polymerase chain reaction assessment of immune reactivity in melanoma patients after tumor peptide vaccination. J. Natl. Cancer Inst. 92, 1336–1344 (2000).

    Article  CAS  Google Scholar 

  15. Phan, G.Q. et al. Immunization of patients with metastatic melanoma using both class I and class II restricted peptides from melanoma-associated antigens. J. Immunother. 26, 349–356 (2003).

    Article  CAS  Google Scholar 

  16. Panelli, M.C. et al. Phase I study in patients with metastatic melanoma of immunization with dendritic cells presenting epitopes derived from the melanoma-associated antigens MART-1 and gp100. J. Immunother. 23, 487–498 (2000).

    Article  CAS  Google Scholar 

  17. Zaks, T.Z. & Rosenberg, S.A. Immunization with a peptide epitope (p369-377) from HER-2/neu leads to peptide-specific cytotoxic T lymphocytes that fail to recognize HER-2/neu+ tumors. Cancer Res. 58, 4902–4908 (1998).

    CAS  PubMed  Google Scholar 

  18. Rosenberg, S.A. et al. Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens. J. Natl. Cancer Inst. 90, 1894–1900 (1998).

    Article  CAS  Google Scholar 

  19. Rosenberg, S.A. et al. Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine. J. Immunol. 163, 1690–1695 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Rosenberg, S.A. et al. Recombinant fowlpox viruses encoding the anchor-modified gp100 melanoma antigen can generate antitumor immune responses in patients with metastatic melanoma. Clin. Cancer Res. 9, 2973–2980 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Rosenberg, S.A. et al. Inability to immunize patients with metastatic melanoma using plasmid DNA encoding the gp100 melanoma-melanocyte antigen. Hum. Gene Ther. 14, 709–714 (2003).

    Article  CAS  Google Scholar 

  22. Thurner, B. et al. Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced staged IV melanoma. J. Exp. Med. 190, 1669–1678 (1999).

    Article  CAS  Google Scholar 

  23. Stift, A. et al. Dendritic cell-based vaccination in solid tumor. J. Clin. Oncol. 21, 135–142 (2003).

    Article  CAS  Google Scholar 

  24. Schriber, H. Tumor Immunology. in Fundamental Immunology (ed. Paul, W.E.) 1557–1592 (Lippincott Williams & Wilkins, Philadelphia, USA, 2003).

    Google Scholar 

  25. Speiser, D.E. et al. Self antigens expressed by solid tumors do not efficiently stimulate naive or activated T cells: implications for immunotherapy. J. Exp. Med. 186, 645–653 (1997).

    Article  CAS  Google Scholar 

  26. Marincola, F.M., Jaffee, E.M., Hicklin, D.J. & Ferrone, S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv. Immunol. 74, 181–273 (2000).

    Article  CAS  Google Scholar 

  27. Klebanoff, C.A. et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc. Natl. Acad. Sci. USA 101, 1969–1974 (2004).

    Article  CAS  Google Scholar 

  28. Von Mehren, M. et al. The influence of granulocyte macrophage colony-stimulating factor and prior chemotherapy on the immunological response to a vaccine (ALVAC-CEA B7.1) in patients with metastatic carcinoma. Clin. Cancer Res. 7, 1181–1191 (2001).

    CAS  PubMed  Google Scholar 

  29. Eder, J.P. et al. A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin. Cancer Res. 6, 1632–1638 (2000).

    CAS  PubMed  Google Scholar 

  30. Rosenberg, S.A. et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat. Med. 4, 321–327 (1998).

    Article  CAS  Google Scholar 

  31. Dudley, M.E. et al. Adoptive transfer of cloned melanoma-reactive T lymphocytes for the treament of patients with metastatic melanoma. J. Immunother. 24, 363–373 (2001).

    Article  CAS  Google Scholar 

  32. Timmerman, J.M. et al. Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients. Blood 99, 1517–1526 (2002).

    Article  CAS  Google Scholar 

  33. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunological self-tolerance maintained by activated T-cells expressing IL-2 receptor alpha-chain (CD25) - Breakdown of a single mechanism of self-tolerance causes various autoimmune-diseases. J. Immunol. 155, 1151–1161 (1995).

    CAS  PubMed  Google Scholar 

  34. Hori, S., Takahashi, T. & Sakaguchi, K. Control of autoimmunity by naturally arising regulatory CD4 cells. Adv. Immunol. 81, 331–371 (2003).

    Article  CAS  Google Scholar 

  35. Shevach, E.M., McHugh, R.S., Piccirillo, C.A. & Thornton, A.M. Control of T-cell activation by CD4+ CD25+ suppressor T cell. Immunol. Rev. 182, 58–67 (2001).

    Article  CAS  Google Scholar 

  36. Morton, D.L. et al. Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine. Ann. Surg. 482 (1992).

  37. Slingluff, C.L. et al. Phase I trial of a melanoma vaccine with gp100280-288 peptide and tetanus helper peptide in adjuvant: immunologic and clinical outcomes. Clin. Cancer Res. 7, 3012–3024 (2001).

    CAS  PubMed  Google Scholar 

  38. Mazzaferro, V. et al. Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin. Cancer Res. 9, 3235–3245 (2003).

    CAS  PubMed  Google Scholar 

  39. Takeda, K., Kaisho, T. & Akira, S. Toll-like receptors. Annu. Rev. Immunol. 21, 335–376 (2003).

    Article  CAS  Google Scholar 

  40. Waldmann, T.A., Dubois, S. & Tagaya, Y. Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 14, 105–110 (2001).

    CAS  PubMed  Google Scholar 

  41. Hodge, J.W. et al. Enhancing the potency of peptide-pulsed antigen presenting cells by vector-driven hyperexpression of a triad of costimulatory molecules. Vaccine 19, 3552–3567 (2001).

    Article  CAS  Google Scholar 

  42. Phan, G.Q. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl. Acad. Sci. USA 100, 8372–8377 (2003).

    Article  CAS  Google Scholar 

  43. Scheibenbogen, C. et al. Phase 2 trial of vaccination with tyrosinase peptides and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma. J. Immunother. 23, 275–281 (2000).

    Article  CAS  Google Scholar 

  44. Slingluff, C.L. et al. Clinical and immunologic results of a randomized phase II trial of vaccination using four melanoma peptides either administered in granulocyte-macrophage colony-stimulating factor in adjuvant or pulsed on dendritic cells. J. Clin. Oncol. 21, 4016–4026 (2003).

    Article  CAS  Google Scholar 

  45. Cebon, J. et al. Two phase I studies of low dose recombinant human IL-12 with Melan-A and influenza peptides in subjects with advanced malignant melanoma. Cancer Immun. 3, 7 (2003).

    PubMed  Google Scholar 

  46. Noguchi, M. et al. Induction of cellular and humoral immune responses to tumor cells and peptides in HLA-A24 positive hormone-refractory prostate cancer patients by peptide vaccination. Prostate 57, 80–92 (2003).

    Article  CAS  Google Scholar 

  47. Peterson, A.C., Harlin, H. & Gajewski, T.F. Immunization with Melan-A peptide-pulsed peripheral blood mononuclear cells plus recombinant human interleukin-12 induces clinical activity and T-cell responses in advanced melanoma. J. Clin. Oncol. 21, 2342–2348 (2003).

    Article  CAS  Google Scholar 

  48. Vonderheide, R.H. et al. Vaccination of cancer patients against telomerase induces functional antitumor CD8+ T lymphocytes. Clin. Cancer Res. 10, 828–839 (2004).

    Article  CAS  Google Scholar 

  49. Van Driel, W.J. et al. Vaccination with HPV16 peptides of patients with advanced cervical carcinoa. Eur. J. Cancer 35, 946–952 (1999).

    Article  CAS  Google Scholar 

  50. Sato, Y. et al. A phase I trial of cytotoxic T-lymphocyte precursor-oriented peptide vaccines for colorectal carcinoma patients. Br. J. Cancer 90, 1334–1342 (2004).

    Article  CAS  Google Scholar 

  51. Jager, E. et al. Induction of primary NY-ESO-1 immunity: CD8+ T lymphocyte and antibody responses in peptide-vaccinated patients with NY-ESO-1+ cancers. Proc. Natl. Acad. Sci. USA 97, 12198–12203 (2000).

    Article  CAS  Google Scholar 

  52. Khleif, S.N. et al. A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors. J. Immunother. 22, 155–165 (1999).

    Article  CAS  Google Scholar 

  53. Tanaka, S. et al. Peptides vaccination for patients with melanoma and other types of cancer based on pre-existing peptide-specific cytotoxic T-lymphocyte precursors in the periphery. J. Immunother. 26, 357–366 (2003).

    Article  CAS  Google Scholar 

  54. Gulley, J. et al. Phase I study of a vaccine using recombinant vaccinia virus expressing PSA (rV-PSA) in patients with metastatic androgen-independent prostate cancer. Prostate 53, 109–117 (2002).

    Article  CAS  Google Scholar 

  55. Conry, R.M. et al. Phase 1 trial of a recombinant vaccinia virus encoding carcinoembryonic antigen in metastatic adenocarcinoma: comparison of intradermal versus subcutaneous administration. Clin. Cancer Res. 5, 2330–2337 (1999).

    CAS  PubMed  Google Scholar 

  56. Horig, H. et al. Phase I clinical trial of a recombinant canarypoxvirus (ALVAC) vaccine expressing human carcinoembryonic antigen and the B7.1 co-stimulatory molecule. Cancer Immunol. Immunother. 49, 504–514 (2000).

    Article  CAS  Google Scholar 

  57. Von Mehren, M. et al. Pilot study of a dual gene recombinant avipox vaccine containing both carcinoembryonic (CEA) and B7.1 transgenes in patients with recurrent CEA-expressing adenocarcinomas. Clin. Cancer Res. 6, 2219–2228 (2000).

    CAS  PubMed  Google Scholar 

  58. Marshall, J.L. et al. Phase I study in cancer patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic antigen. J. Clin. Oncol. 17, 332–337 (1999).

    Article  CAS  Google Scholar 

  59. Marshall, J.L. et al. Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses. J. Clin. Oncol. 18, 3964–3973 (2000).

    Article  CAS  Google Scholar 

  60. Soiffer, R. et al. 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 (1998).

    Article  CAS  Google Scholar 

  61. Mitchell, M.S. et al. Phase I trial of large multivalent immunogen derived from melanoma lysates in patients with disseminated melanoma. Clin. Cancer Res. 10, 76–83 (2004).

    Article  CAS  Google Scholar 

  62. Salgia, R. et al. Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma. J. Clin. Oncol. 21, 624–630 (2003).

    Article  Google Scholar 

  63. Neumunaitis, J. et al. Granulocyte-macrophage colony-stimulating factor gene-modified autologous tumor vaccines in non-small-cell lung cancer. J. Natl. Cancer Inst. 96, 326–331 (2004).

    Article  Google Scholar 

  64. Dols, A. et al. Vaccination of women with metastatic breast cancer, using a costimulatory gene (CD80)-modified, HLA-A2 matched, allogeneic, breast cancer cell line: clinical and immunological results. Hum. Gene Ther. 14, 1117–1123 (2003).

    Article  CAS  Google Scholar 

  65. Banchereau, J. et al. Immune and clinical responses in patients with metastatic melanoma to CD34+ progenitor-derived dendritic cell vaccine. Cancer Res. 61, 6451–6458 (2001).

    CAS  Google Scholar 

  66. Hersey, P. et al. Phase I/II study of treatment with dendritic cell vaccines in patients with disseminated melanoma. Cancer Immunol. Immunother. 53, 125–134 (2003).

    Article  Google Scholar 

  67. Nestle, F.O. et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat. Med. 4, 328–332 (1998).

    Article  CAS  Google Scholar 

  68. Schuler-Thurner, B. et al. Rapid induction of tumor-specific type 1 T helper cells in metastatic melanoma patients by vaccination with mature, cryopreserved, peptide-loaded monocyte-derived dendritic cells. J. Exp. Med. 195, 1279–1288 (2002).

    Article  CAS  Google Scholar 

  69. Geiger, J.D. et al. Vaccination of pediatric solid tumor patients with tumor lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res. 61, 8513–8519 (2001).

    CAS  Google Scholar 

  70. Su, Z. et al. Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumor RNA-transfected dendritic cells. Cancer Res. 63, 2128–2133 (2003).

    Google Scholar 

  71. Fong, L. et al. Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc. Natl. Acad. Sci. USA 98, 8809–8814 (2001).

    Article  CAS  Google Scholar 

  72. Holtl, L. et al. Immunotherapy of metastatic renal cell carcinoma with tumor lysate-pulsed autologous dendritic cells. Clin. Cancer Res. 8, 3369–3376 (2002).

    CAS  PubMed  Google Scholar 

  73. Belli, F. et al. Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings. J. Clin. Oncol. 20, 4169–4180 (2002).

    Article  CAS  Google Scholar 

  74. Janetzki, S. et al. Immunization of cancer patients with autologous cancer-derived heat schock protein gp96 preparations: a pilot study. Int. J. Cancer 88, 232–238 (2000).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Steven A Rosenberg.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rosenberg, S., Yang, J. & Restifo, N. Cancer immunotherapy: moving beyond current vaccines. Nat Med 10, 909–915 (2004). https://doi.org/10.1038/nm1100

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1100

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing