Skip to main content

Advertisement

Log in

Induction of cellular immune responses against carcinoembryonic antigen in patients with metastatic tumors after vaccination with altered peptide ligand-loaded dendritic cells

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose: Dendritic cells (DCs) are characterized by their extraordinary capacity to induce T-cell responses, providing the opportunity of DC-based cancer vaccination protocols. In the present study, we conducted a phase I/II clinical trial to determine the capability of DCs differentiated from immunomagnetically isolated CD14+ monocytes and pulsed with a carcinoembyonic antigen-derived altered peptide (CEAalt) to induce specific CD8+ T cells in cancer patients. Experimental design: Nine patients with CEA-positive colorectal cancer (n=7) or lung cancer (n=2) were enrolled in this study. Autologous CD14+ monocytes were isolated by large-scale immunomagnetic separation and differentiated to mature DCs in sufficient numbers and at high purity. After incubation with the CEAalt peptide and keyhole limpet hemocyanin, DCs were administered to patients intravenously at dose levels of 1×107 and 5×107 cells. Patients received four immunizations every second week. Results: ELISPOT analysis revealed a vaccine-induced increase in the number of CEAalt peptide-specific Interferon (IFN)-gamma producing CD8+ T cells in five of nine patients and of CD8+ T lymphocytes recognizing the native CEA peptide in three of nine patients. In addition, CD8+ T lymphocytes derived from one patient exhibiting an immunological response after vaccination efficiently lysed peptide-loaded T2 cells and tumor cells. Immunization was well tolerated by all patients without severe signs of toxicity. Conclusion: Vaccination with CEAalt-pulsed DCs derived from immunomagnetically isolated CD14+ monocytes efficiently expand peptide-specific CD8+ T lymphocytes in vivo and may be a promising alternative for cancer immunotherapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Babatz J, Rollig C, Oelschlagel U, Zhao S, Ehninger G, Schmitz M, Bornhauser M (2003) Large-scale immunomagnetic selection of CD14+ monocytes to generate dendritic cells for cancer immunotherapy: a phase I study. J Hematother Stem Cell Res 12:515–523

    Article  PubMed  CAS  Google Scholar 

  2. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811

    Article  PubMed  CAS  Google Scholar 

  3. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    Article  PubMed  CAS  Google Scholar 

  4. Bender A, Sapp M, Schuler G, Steinman RM, Bhardwaj N (1996) Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. J Immunol Meth 196:121–135

    Article  CAS  Google Scholar 

  5. Cao H, Verge V, Baron C, Martinache C, Leon A, Scholl S, Gorin NC, Salamero J, Assari S, Bernard J, Lopez M (2000) In vitro generation of dendritic cells from human blood monocytes in experimental conditions compatible for in vivo cell therapy. J Hematother Stem Cell Res 9:183–194

    Article  PubMed  CAS  Google Scholar 

  6. Chomarat P, Banchereau J, Davoust J, Palucka AK (2000) IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol 1:510–514

    Article  PubMed  CAS  Google Scholar 

  7. Cranmer LD, Trevor KT, Hersh EM (2004) Clinical applications of dendritic cell vaccination in the treatment of cancer. Cancer Immunol Immunother 53:275–306

    Article  PubMed  Google Scholar 

  8. Dhodapkar MV, Krasovsky J, Steinman RM, Bhardwaj N (2000) Mature dendritic cells boost functionally superior CD8(+) T-cell in humans without foreign helper epitopes. J Clin Invest 105:R9–R14

    Article  PubMed  CAS  Google Scholar 

  9. Dhodapkar MV, Steinman RM, Sapp M, Desai H, Fossella C, Krasovsky J, Donahoe SM, Dunbar PR, Cerundolo V, Nixon DF, Bhardwaj N (1999) Rapid generation of broad T-cell immunity in humans after a single injection of mature dendritic cells. J Clin Invest 104:173–180

    PubMed  CAS  Google Scholar 

  10. Fong L, Engleman EG (2000) Dendritic cells in cancer immunotherapy. Annu Rev Immunol 18:245–273

    Article  PubMed  CAS  Google Scholar 

  11. Fong L, Hou Y, Rivas A, Benike C, Yuen A, Fisher GA, Davis MM, Engleman EG (2001) Altered peptide ligand vaccination with Flt3 ligand expanded dendritic cells for tumor immunotherapy. Proc Natl Acad Sci U S A 98:8809–8814

    Article  PubMed  CAS  Google Scholar 

  12. Garrido F, Cabrera T, Concha A, Glew S, Ruiz-Cabello F, Stern PL (1993) Natural history of HLA expression during tumour development. Immunol Today 14:491–499

    Article  PubMed  CAS  Google Scholar 

  13. Goxe B, Latour N, Chokri M, Abastado JP, Salcedo M (2000) Simplified method to generate large quantities of dendritic cells suitable for clinical applications. Immunol Invest 29:319–336

    PubMed  CAS  Google Scholar 

  14. Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Lienard D, Cerottini J, Tschopp J (1996) Melanoma cell expression of Fas(Apo-1/CD95) ligand: implications for tumor immune escape. Science 274:1363–1366

    Article  PubMed  CAS  Google Scholar 

  15. Hart DN (1997) Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 90:3245–3287

    PubMed  CAS  Google Scholar 

  16. Holtl L, Ramoner R, Zelle-Rieser C, Gander H, Putz T, Papesh C, Nussbaumer W, Falkensammer C, Bartsch G, Thurnher M (2004) Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide. Cancer Immunol Immunother

  17. Itoh T, Ueda Y, Kawashima I, Nukaya I, Fujiwara H, Fuji N, Yamashita T, Yoshimura T, Okugawa K, Iwasaki T, Ideno M, Takesako K, Mitsuhashi M, Orita K, Yamagishi H (2002) Immunotherapy of solid cancer using dendritic cells pulsed with the HLA-A24-restricted peptide of carcinoembryonic antigen. Cancer Immunol Immunother 51:99–106

    Article  PubMed  CAS  Google Scholar 

  18. Kessler BM, Bassanini P, Cerottini JC, Luescher IF (1997) Effects of epitope modification on T cell receptor-ligand binding and antigen recognition by seven H-2Kd-restricted cytotoxic T lymphocyte clones specific for a photoreactive peptide derivative. J Exp Med 185:629–640

    Article  PubMed  CAS  Google Scholar 

  19. Kiessling A, Schmitz M, Stevanovic S, Weigle B, Holig K, Fussel M, Fussel S, Meye A, Wirth MP, Rieber EP (2002) Prostate stem cell antigen: identification of immunogenic peptides and assessment of reactive CD8+ T cells in prostate cancer patients. Int J Cancer 102:390–397

    Article  PubMed  CAS  Google Scholar 

  20. Langenkamp A, Messi M, Lanzavecchia A, Sallusto F (2000) Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat Immunol 1:311–316

    Article  PubMed  CAS  Google Scholar 

  21. Liu KJ, Wang CC, Chen LT, Cheng AL, Lin DT, Wu YC, Yu WL, Hung YM, Yang HY, Juang SH, Whang-Peng J (2004) Generation of carcinoembryonic antigen (CEA)-specific T-cell responses in HLA-A*0201 and HLA-A*2402 late-stage colorectal cancer patients after vaccination with dendritic cells loaded with CEA peptides. Clin Cancer Res 10:2645–2651

    Article  PubMed  CAS  Google Scholar 

  22. Markiewicz MA, Kast WM (2004) Progress in the development of immunotherapy of cancer using ex vivo-generated dendritic cells expressing multiple tumor antigen epitopes. Cancer Invest 22:417–434

    Article  PubMed  CAS  Google Scholar 

  23. Matsuda K, Tsunoda T, Tanaka H, Umano Y, Tanimura H, Nukaya I, Takesako K, Yamaue H (2004) Enhancement of cytotoxic T-lymphocyte responses in patients with gastrointestinal malignancies following vaccination with CEA peptide-pulsed dendritic cells. Cancer Immunol Immunother 53:609–616

    Article  PubMed  CAS  Google Scholar 

  24. Mayordomo JI, Zorina T, Storkus WJ, Zitvogel L, Celluzzi C, Falo LD, Melief CJ, Ildstad ST, Kast WM, Deleo AB (1995) Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nat Med 1:1297–1302

    Article  PubMed  CAS  Google Scholar 

  25. Millard AL, Ittelet D, Schooneman F, Bernard J (2003) Dendritic cell KLH loading requirements for efficient CD4+ T-cell priming and help to peptide-specific cytotoxic T-cell response, in view of potential use in cancer vaccines. Vaccine 21:869–876

    Article  PubMed  CAS  Google Scholar 

  26. Motta MR, Castellani S, Rizzi S, Curti A, Gubinelli F, Fogli M, Ferri E, Cellini C, Baccarani M, Lemoli RM (2003) Generation of dendritic cells from CD14+ monocytes positively selected by immunomagnetic adsorption for multiple myeloma patients enrolled in a clinical trial of anti-idiotype vaccination. Br J Haematol 121:240–250

    Article  PubMed  Google Scholar 

  27. Nair SK, Heiser A, Boczkowski D, Majumdar A, Naoe M, Lebkowski JS, Vieweg J, Gilboa E (2000) Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. Nat Med 6:1011–1017

    Article  PubMed  CAS  Google Scholar 

  28. Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D (1998) Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4:328–332

    Article  PubMed  CAS  Google Scholar 

  29. Padley DJ, Dietz AB, Gastineau DA, Vuk-Pavlovic S (2001) Mature myeloid dendritic cells for clinical use prepared from CD14+ cells isolated by immunomagnetic adsorption. J Hematother Stem Cell Res 10:427–429

    Article  PubMed  CAS  Google Scholar 

  30. Ridge JP, Di Rosa F, Matzinger P (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393:474–478

    Article  PubMed  CAS  Google Scholar 

  31. Salazar E, Zaremba S, Arlen PM, Tsang KY, Schlom J (2000) Agonist peptide from a cytotoxic t-lymphocyte epitope of human carcinoembryonic antigen stimulates production of tc1-type cytokines and increases tyrosine phosphorylation more efficiently than cognate peptide. Int J Cancer 85:829–838

    Article  PubMed  CAS  Google Scholar 

  32. Sallusto F, Lanzavecchia A (1994) Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 179:1109–1118

    Article  PubMed  CAS  Google Scholar 

  33. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393:480–483

    Article  PubMed  CAS  Google Scholar 

  34. Schuler-Thurner B, Schultz ES, Berger TG, Weinlich G, Ebner S, Woerl P, Bender A, Feuerstein B, Fritsch PO, Romani N, Schuler G (2002) 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

    Article  PubMed  CAS  Google Scholar 

  35. Spisek R, Bretaudeau L, Barbieux I, Meflah K, Gregoire M (2001) Standardized generation of fully mature p70 IL-12 secreting monocyte-derived dendritic cells for clinical use. Cancer Immunol Immunother 50:417–427

    Article  PubMed  CAS  Google Scholar 

  36. 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 190:1669–1678

    Article  PubMed  CAS  Google Scholar 

  37. 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 223:1–15

    Article  PubMed  CAS  Google Scholar 

  38. Wang RF (2001) The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity. Trends Immunol 22:269–276

    Article  PubMed  Google Scholar 

  39. Yu Z, Restifo NP (2002) Cancer vaccines: progress reveals new complexities. J Clin Invest 110:289–294

    Article  PubMed  CAS  Google Scholar 

  40. Zaremba S, Barzaga E, Zhu M, Soares N, Tsang KY, Schlom J (1997) Identification of an enhancer agonist cytotoxic T lymphocyte peptide from human carcinoembryonic antigen. Cancer Res 57:4570–4577

    PubMed  CAS  Google Scholar 

  41. Zehn D, Cohen CJ, Reiter Y, Walden P (2004) Extended presentation of specific MHC-peptide complexes by mature dendritic cells compared to other types of antigen-presenting cells. Eur J Immunol 34:1551–1560

    Article  PubMed  CAS  Google Scholar 

  42. Zugel U, Wang R, Shih G, Sette A, Alexander J, Grey HM (1998) Termination of peripheral tolerance to a T cell epitope by heteroclitic antigen analogues. J Immunol 161:1705–1709

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank V. Schwarze, A. Maiwald, A. Weiske and D. Döhler for their technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christoph Röllig.

Additional information

Jana Babatz and Christoph Röllig contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Cite this article

Babatz, J., Röllig, C., Löbel, B. et al. Induction of cellular immune responses against carcinoembryonic antigen in patients with metastatic tumors after vaccination with altered peptide ligand-loaded dendritic cells. Cancer Immunol Immunother 55, 268–276 (2006). https://doi.org/10.1007/s00262-005-0021-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-005-0021-x

Keywords

Navigation