Cancer Immunology, Immunotherapy

, Volume 53, Issue 7, pp 633–641 | Cite as

Vaccination with p53-peptide–pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study

  • Inge Marie Svane
  • Anders E. Pedersen
  • Hans E. Johnsen
  • Dorte Nielsen
  • Claus Kamby
  • Eva Gaarsdal
  • Kirsten Nikolajsen
  • Søren Buus
  • Mogens H. Claesson
Original Article


Peptides derived from over-expressed p53 protein are presented by class I MHC molecules and may act as tumour-associated epitopes. Due to the diversity of p53 mutations, immunogenic peptides representing wild-type sequences are preferable as a basis for a broad-spectrum p53-targeting cancer vaccine. Our preclinical studies have shown that wild-type p53-derived HLA-A2–binding peptides are able to activate human T cells and that the generated effector T cells are cytotoxic to human HLA-A2+, p53+ tumour cells. In this phase I pilot study, the toxicity and efficacy of autologous dendritic cells (DCs) loaded with a cocktail of three wild-type and three modified p53 peptides are being analysed in six HLA-A2+ patients with progressive advanced breast cancer. Vaccinations were well tolerated and no toxicity was observed. Disease stabilisation was seen in two of six patients, one patient had a transient regression of a single lymph node and one had a mixed response. ELISpot analyses showed that the p53-peptide–loaded DCs were able to induce specific T-cell responses against modified and unmodified p53 peptides in three patients, including two of the patients with a possible clinical benefit from the treatment. In conclusion, the strategy for p53-DC vaccination seems safe and without toxicity. Furthermore, indications of both immunologic and clinical effect were found in heavily pretreated patients with advanced breast cancer. An independent clinical effect of repeated administration of DCs and IL-2 can not of course be excluded; further studies are necessary to answer these questions.


Dendritic cells Breast cancer Vaccine p53 peptides Immunotherapy 



This work was supported by grants from The Danish Cancer Research Foundation, The Danish Cancer Society, The Michaelsen Foundation and The Aase og Ejnar Danielsen’s Foundation.


  1. 1.
    Alexander J, Fikes J, Hoffman S, Franke E, Sacci J, Appella E, Chisari FV, Guidotti LG, Chesnut RW, Livingston B, Sette A (1998) The optimization of helper T lymphocyte (HTL) function in vaccine development. Immunol Res 18:79PubMedGoogle Scholar
  2. 2.
    Andersen MH, Gehl J, Reker S, Pedersen LO, Becker JC, Geertsen P, Straten PT (2003) Dynamic changes of specific T cell responses to melanoma correlate with IL-2 administration. Semin Cancer Biol (in press)Google Scholar
  3. 3.
    Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767PubMedGoogle Scholar
  4. 4.
    Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A, Taquet S, Coquery S, Wittkowski KM, Bhardwaj N, Pineiro L, Steinman R, Fay J (2001) Immune and clinical responses in patients with metastatic melanoma to CD34+ progenitor-derived dendritic cell vaccine. Cancer Res 61:6451PubMedGoogle Scholar
  5. 5.
    Barfoed AM, Petersen TR, Kirkin AF, thor SP, Claesson MH, Zeuthen J (2000) Cytotoxic T-lymphocyte clones, established by stimulation with the HLA-A2 binding p5365–73 wild type peptide loaded on dendritic cells in vitro, specifically recognize and lyse HLA-A2 tumour cells overexpressing the p53 protein. Scand J Immunol 51:128CrossRefPubMedGoogle Scholar
  6. 6.
    Chang F, Syrjanen S, Syrjanen K (1995) Implications of the p53 tumor-suppressor gene in clinical oncology. J Clin Oncol 13:1009PubMedGoogle Scholar
  7. 7.
    Chariyalertsak S, Cheirsilpa A, Chindavijak K (1998) Prognostic importance of p53 and c-erbB-2 oncoproteins overexpression in patients with breast cancer. J Med Assoc Thai 81:698PubMedGoogle Scholar
  8. 8.
    Coulie PG, Karanikas V, Colau D, Lurquin C, Landry C, Marchand M, Dorval T, Brichard V, Boon T (2001) A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3. Proc Natl Acad Sci USA 98:10290PubMedGoogle Scholar
  9. 9.
    De Vries IJ, Eggert AA, Scharenborg NM, Vissers JL, Lesterhuis WJ, Boerman OC, Punt CJ, Adema GJ, Figdor CG (2002) Phenotypical and functional characterization of clinical grade dendritic cells. J Immunother 25:429CrossRefPubMedGoogle Scholar
  10. 10.
    Dhodapkar MV, Steinman RM (2002) Antigen-bearing immature dendritic cells induce peptide-specific CD8(+) regulatory T cells in vivo in humans. Blood 100:174CrossRefPubMedGoogle Scholar
  11. 11.
    Eura M, Chikamatsu K, Katsura F, Obata A, Sobao Y, Takiguchi M, Song Y, Appella E, Whiteside TL, DeLeo AB (2000) A wild-type sequence p53 peptide presented by HLA-A24 induces cytotoxic T lymphocytes that recognize squamous cell carcinomas of the head and neck. Clin Cancer Res 6:979PubMedGoogle Scholar
  12. 12.
    Feuerstein B, Berger TG, Maczek C, Roder C, Schreiner D, Hirsch U, Haendle I, Leisgang W, Glaser A, Kuss O, Diepgen TL, Schuler G, Schuler-Thurner B (2000) A method for the production of cryopreserved aliquots of antigen-preloaded, mature dendritic cells ready for clinical use. J Immunol Methods 245:15CrossRefPubMedGoogle Scholar
  13. 13.
    Fong L, Engleman EG (2000) Dendritic cells in cancer immunotherapy. Annu Rev Immunol 18:245PubMedGoogle Scholar
  14. 14.
    Gnjatic S, Cai Z, Viguier M, Chouaib S, Guillet JG, Choppin J (1998) Accumulation of the p53 protein allows recognition by human CTL of a wild-type p53 epitope presented by breast carcinomas and melanomas. J Immunol 160:328PubMedGoogle Scholar
  15. 15.
    Jager E, Ringhoffer M, Altmannsberger M, Arand M, Karbach J, Jager D, Oesch F, Knuth A (1997) Immunoselection in vivo: independent loss of MHC class I and melanocyte differentiation antigen expression in metastatic melanoma. Int J Cancer 71:142CrossRefPubMedGoogle Scholar
  16. 16.
    Jager E, Gnjatic S, Nagata Y, Stockert E, Jager D, Karbach J, Neumann A, Rieckenberg J, Chen YT, Ritter G, Hoffman E, Arand M, Old LJ, Knuth A (2000) 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 97:12198PubMedGoogle Scholar
  17. 17.
    James K, Eisenhauer E, Christian M, Terenziani M, Vena D, Muldal A, Therasse P (1999) Measuring response in solid tumors: unidimensional versus bidimensional measurement. J Natl Cancer Inst 91:523CrossRefPubMedGoogle Scholar
  18. 18.
    Lutzker SG, Lattime EC (2001) Use of dendritic cells to immunize against cancers overexpressing p53. Clin Cancer Res 7:2PubMedGoogle Scholar
  19. 19.
    Mendez R, Serrano A, Jager E, Maleno I, Ruiz-Cabello F, Knuth A, Garrido F (2001) Analysis of HLA class I expression in different metastases from two melanoma patients undergoing peptide immunotherapy. Tissue Antigens 57:508CrossRefPubMedGoogle Scholar
  20. 20.
    Nikitina EY, Clark JI, Van Beynen J, Chada S, Virmani AK, Carbone DP, Gabrilovich DI (2001) Dendritic cells transduced with full-length wild-type p53 generate antitumor cytotoxic T lymphocytes from peripheral blood of cancer patients. Clin Cancer Res 7:127PubMedGoogle Scholar
  21. 21.
    O’Rourke MG, Johnson M, Lanagan C, See J, Yang J, Bell JR, Slater GJ, Kerr BM, Crowe B, Purdie DM, Elliott SL, Ellem KA, Schmidt CW (2003) Durable complete clinical responses in a phase I/II trial using an autologous melanoma cell/dendritic cell vaccine. Cancer Immunol Immunother 52:387PubMedGoogle Scholar
  22. 22.
    Petersen TR, Buus S, Brunak S, Nissen MH, Sherman LA, Claesson MH (2001) Identification and design of p53-derived HLA-A2-binding peptides with increased CTL immunogenicity. Scand J Immunol 53:357CrossRefPubMedGoogle Scholar
  23. 23.
    Reid DC (2001) Dendritic cells and immunotherapy for malignant disease. Br J Haematol 112:874PubMedGoogle Scholar
  24. 24.
    Ropke M, Hald J, Guldberg P, Zeuthen J, Norgaard L, Fugger L, Svejgaard A, Van der BS, Nijman HW, Melief CJ, Claesson MH (1996) Spontaneous human squamous cell carcinomas are killed by a human cytotoxic T lymphocyte clone recognizing a wild-type p53-derived peptide. Proc Natl Acad Sci USA 93:14704CrossRefPubMedGoogle Scholar
  25. 25.
    Rosenberg SA (2001) Progress in human tumour immunology and immunotherapy. Nature 411:380PubMedGoogle Scholar
  26. 26.
    Soussi T (2000) The p53 tumor suppressor gene: from molecular biology to clinical investigation. Ann N Y Acad Sci 910:121PubMedGoogle Scholar
  27. 27.
    Svane IM, Soot ML, Buus S, Johnsen HE (2003) Clinical application of dendritic cells in cancer vaccination therapy. APMIS 111:818CrossRefPubMedGoogle Scholar
  28. 28.
    Theobald M, Biggs J, Dittmer D, Levine AJ, Sherman LA (1995) Targeting p53 as a general tumor antigen. Proc Natl Acad Sci USA 92:11993PubMedGoogle Scholar
  29. 29.
    Theobald M, Biggs J, Hernandez J, Lustgarten J, Labadie C, Sherman LA (1997) Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes. J Exp Med 185:833PubMedGoogle Scholar
  30. 30.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205PubMedGoogle Scholar
  31. 31.
    Thurner B, Haendle I, Roder C, Dieckmann D, Keikavoussi P, Jonuleit H, Bender A, Maczek C, Schreiner D, von den DP, Brocker EB, Steinman RM, Enk A, Kampgen E, Schuler G (1999) Vaccination with mage-3A1 peptide-pulsed mature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma. J Exp Med 190:1669PubMedGoogle Scholar
  32. 32.
    Thurner B, Roder C, Dieckmann D, Heuer M, Kruse M, Glaser A, Keikavoussi P, Kampgen E, Bender A, Schuler G (1999) Generation of large numbers of fully mature and stable dendritic cells from leukapheresis products for clinical application. J Immunol Methods 223:1PubMedGoogle Scholar
  33. 33.
    Vierboom MP, Zwaveling S, Bos GMJ, Ooms M, Krietemeijer GM, Melief CJ, Offringa R (2000) High steady-state levels of p53 are not a prerequisite for tumor eradication by wild-type p53-specific cytotoxic T lymphocytes. Cancer Res 60:5508PubMedGoogle Scholar
  34. 34.
    Wurtzen PA, Claesson MH (2002) A HLA-A2 restricted human CTL line recognizes a novel tumor cell expressed p53 epitope. Int J Cancer 99:568CrossRefPubMedGoogle Scholar
  35. 35.
    Wurtzen PA, Pedersen LO, Poulsen HS, Claesson MH (2001) Specific killing of P53 mutated tumor cell lines by a cross-reactive human HLA-A2-restricted P53-specific CTL line. Int J Cancer 93:855CrossRefPubMedGoogle Scholar
  36. 36.
    Zwaveling S, Vierboom MP, Ferreira Mota SC, Hendriks JA, Ooms ME, Sutmuller RP, Franken KL, Nijman HW, Ossendorp F, van der Burg SH, Offringa R, Melief CJ (2002) Antitumor efficacy of wild-type p53-specific CD4(+) T-helper cells. Cancer Res 62:6187Google Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Inge Marie Svane
    • 1
    • 2
  • Anders E. Pedersen
    • 3
  • Hans E. Johnsen
    • 2
  • Dorte Nielsen
    • 1
  • Claus Kamby
    • 1
  • Eva Gaarsdal
    • 2
  • Kirsten Nikolajsen
    • 2
  • Søren Buus
    • 3
  • Mogens H. Claesson
    • 3
  1. 1.Department of OncologyHerlev University HospitalHerlevDenmark
  2. 2.Department of HematologyHerlev University HospitalHerlevDenmark
  3. 3.Panum InstituteUniversity of CopenhagenCopenhagenDenmark

Personalised recommendations