Skip to main content

Advertisement

SpringerLink
Log in

Immuno-gene therapy of cancer with tumour-mRNA transfected dendritic cells

  • Symposium Paper
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

We have developed immuno-gene therapy for malignant melanoma and prostate cancer. The therapy is based on monocyte-derived dendritic cells (DCs) that are transfected with autologous melanoma-mRNA or mRNA from three prostate cancer cell lines (DU-145, LN-CaP and PC-3). A broad spectrum of tumour-associated antigens will be included in both DC-vaccines. The use of autologous melanoma-mRNA moreover allows targeting of individual tumour antigens that are specific to each patient. Effective protocols have been established for mRNA-transfection by square wave electroporation and for the generation of clinical grade DCs. A full scale preclinical evaluation demonstrated in vitro T cell responses in 6/6 advanced melanoma patients. The responses were specific to antigens encoded by the transfected tumour-mRNA. Recently, we have conducted two phase I/II trials, in advanced malignant melanoma and androgen-resistant prostate cancer. Successful vaccine preparations were obtained for all 41 patients elected. No serious adverse effects were observed. Specific T cell responses (T cell proliferation and/or IFNγ ELISPOT) were demonstrated in 9/19 evaluable melanoma patients and in 12/19 prostate cancer patients. The response rates were higher for patients receiving intradermal vaccination, compared to intranodal injection. Thirteen prostate cancer patients developed a decrease in log-slope PSA. The PSA-response was significantly related to the T cell response (P=0.002). We conclude that the DC-vaccine is feasible and safe, and that T cell responses are elicited in about 50% of patients.

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

Access this article

Log in via an institution

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

Abbreviations

DC:

Dendritic cell

PBMC:

Peripheral blood mononuclear cell

EGFP:

Enhanced green fluorescent protein

hTERT:

Human telomerase reverse transcriptase

TRAP:

Telomeric repeat amplification protocol

EBV-cells:

Epstein Barr virus-transformed cell-lines

PSA:

Prostate specific antigen

TLR:

Toll-like receptor

References

  1. Anichini A, Mortarini R, Maccalli C, Squarcina P, Fleischhauer K, Mascheroni L, Parmiani G (1996) Cytotoxic T cells directed to tumour antigens not expressed on normal melanocytes dominate HLA-A2.1-restricted immune repertoire to melanoma. J Immunol 156:208–217

    PubMed  CAS  Google Scholar 

  2. Banchereau J, Palucka AK (2005) Dendritic cells as therapeutic vaccines against cancer. Nat Rev Cancer 5:296–306

    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. 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 61:6451–6458

    PubMed  CAS  Google Scholar 

  5. Boczkowski D, Nair SK, Nam JH, Lyerly HK, Gilboa E (2000) Induction of tumour immunity and cytotoxic T lymphocyte responses using dendritic cells transfected with messenger RNA amplified from tumour cells. Cancer Res 60:1028–1034

    PubMed  CAS  Google Scholar 

  6. Brunsvig P, Aamdal S, Gjertsen MK, Kvalheim G, Markowski-Grimsrud CJ, Sve I, Dyrhaug M, Trachsel S, Moeller M, Eriksen JA, Gaudernack G (2006) Telomerase peptide vaccination: a phase I/II study in patients with non-small cell lung cancer. Cancer Immunol Immunother (Epub ahead of print Feb 21)

  7. Burnet FM (1970) The concept of immunological surveillance. Prog Exp Tumour Res 13:1–27

    CAS  Google Scholar 

  8. Burns RP Jr, Ferbel B, Tomai M, Miller R, Gaspari AA (2000) The imidazoquinolines, imiquimod and R-848, induce functional, but not phenotypic, maturation of human epidermal Langerhans’ cells. Clin Immunol 94:13–23

    Article  PubMed  CAS  Google Scholar 

  9. Caruso DA, Orme LM, Neale AM, Radcliff FJ, Amor GM, Maixner W, Downie P, Hassall TE, Tang ML, Ashley DM (2004) Results of a phase 1 study utilizing monocyte-derived dendritic cells pulsed with tumour RNA in children and young adults with brain cancer. Neuro-oncol 6:236–246

    Article  PubMed  CAS  Google Scholar 

  10. Caruso DA, Orme LM, Amor GM, Neale AM, Radcliff FJ, Downie P, Tang ML, Ashley DM (2005) Results of a phase I study utilizing monocyte-derived dendritic cells pulsed with tumour RNA in children with stage 4 neuroblastoma. Cancer 103:1280–1291

    Article  PubMed  CAS  Google Scholar 

  11. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  PubMed  CAS  Google Scholar 

  12. Dannull J, Su Z, Rizzieri D, Yang BK, Coleman D, Yancey D, Zhang A, Dahm P, Chao N, Gilboa E, Vieweg J (2005) Enhancement of vaccine-mediated antitumour immunity in cancer patients after depletion of regulatory T cells. J Clin Invest 115:3623–3633

    Article  PubMed  CAS  Google Scholar 

  13. De Vries IJ, Krooshoop DJ, Scharenborg NM, Lesterhuis WJ, Diepstra JH, Van Muijen GN, Strijk SP, Ruers TJ, Boerman OC, Oyen WJ, Adema GJ, Punt CJ, Figdor CG (2003) Effective migration of antigen-pulsed dendritic cells to lymph nodes in melanoma patients is determined by their maturation state. Cancer Res 63:12–17

    PubMed  Google Scholar 

  14. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumour escape. Nat Immunol 3:991–998

    Article  PubMed  CAS  Google Scholar 

  15. Figdor CG, De Vries IJ, Lesterhuis WJ, Melief CJ (2004) Dendritic cell immunotherapy: mapping the way. Nat Med 10:475–480

    Article  PubMed  CAS  Google Scholar 

  16. Gilboa E, Vieweg J (2004) Cancer immunotherapy with mRNA-transfected dendritic cells. Immunol Rev 199:251–263

    Article  PubMed  CAS  Google Scholar 

  17. Gong J, Nikrui N, Chen D, Koido S, Wu Z, Tanaka Y, Cannistra S, Avigan D, Kufe D (2000) Fusions of human ovarian carcinoma cells with autologous or allogeneic dendritic cells induce antitumour immunity. J Immunol 165:1705–1711

    PubMed  CAS  Google Scholar 

  18. Heiser A, Coleman D, Dannull J, Yancey D, Maurice MA, Lallas CD, Dahm P, Niedzwiecki D, Gilboa E, Vieweg J (2002) Autologous dendritic cells transfected with prostate-specific antigen RNA stimulate CTL responses against metastatic prostate tumours. J Clin Invest 109:409–417

    Article  PubMed  CAS  Google Scholar 

  19. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol 3:196–200

    Article  PubMed  CAS  Google Scholar 

  20. Hirschowitz EA, Foody T, Kryscio R, Dickson L, Sturgill J, Yannelli J (2004) Autologous dendritic cell vaccines for non-small-cell lung cancer. J Clin Oncol 22:2808–2815

    Article  PubMed  Google Scholar 

  21. Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. PNAS 100:4712–4717

    Article  PubMed  CAS  Google Scholar 

  22. Jarnjak-Jankovic S, Pettersen RD, Saeboe-Larssen S, Wesenberg F, Olafsen MR, Gaudernack G (2005) Preclinical evaluation of autologous dendritic cells transfected with mRNA or loaded with apoptotic cells for immunotherapy of high-risk neuroblastoma. Cancer Gene Ther 12:699–707

    Article  PubMed  CAS  Google Scholar 

  23. Kaufman HL, Wang W, Manola J, DiPaola RS, Ko YJ, Sweeney C, Whiteside TL, Schlom J, Wilding G, Weiner LM (2004) Phase II randomized study of vaccine treatment of advanced prostate cancer (E7897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 22:2122–2132

    Article  PubMed  CAS  Google Scholar 

  24. Kyte JA, Kvalheim G, Aamdal S, Saebøe-Larssen S, Gaudernack G (2005) Preclinical full-scale evaluation of dendritic cells transfected with autologous tumour-mRNA for melanoma vaccination. Cancer Gene Ther 12:579–591

    Article  PubMed  CAS  Google Scholar 

  25. Kyte JA, Mu LJ, Aamdal S, Kvalheim G, Dueland S, Hauser M, Gullestad HP, Ryder T, Lislerud K, Hammerstad H, Gaudernack G (2006) Phase I/II trial of melanoma therapy with dendritic cells transfected with autologous tumour-mRNA. Cancer Gene Ther (in press)

  26. Marchand M, Weynants P, Rankin E, Arienti F, Belli F, Parmiani G, Cascinelli N, Bourlond A, Vanwijck R, Humblet Y et al (1995) Tumour regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int J Cancer 63:883–885

    Article  PubMed  CAS  Google Scholar 

  27. Morse MA, Coleman RE, Akabani G, Niehaus N, Coleman D, Lyerly HK (1999) Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res 59:56–58

    PubMed  CAS  Google Scholar 

  28. Morse MA, Nair SK, Mosca PJ, Hobeika AC, Clay TM, Deng Y, Boczkowski D, Proia A, Neidzwiecki D, Clavien PA, Hurwitz HI, Schlom J, Gilboa E, Lyerly HK (2003) Immunotherapy with autologous, human dendritic cells transfected with carcinoembryonic antigen mRNA. Cancer Invest 21:341–349

    Article  PubMed  CAS  Google Scholar 

  29. Mu LJ, Gaudernack G, Saebøe-Larssen S, Hammerstad H, Tierens A, Kvalheim G (2003) A protocol for generation of clinical grade mRNA-transfected monocyte-derived dendritic cells for cancer vaccines. Scand J Immunol 58:578–586

    Article  PubMed  CAS  Google Scholar 

  30. Mu LJ, Kyte JA, Kvalheim G, Aamdal S, Dueland S, Hauser M, Hammerstad H, Waehre H, Raabe N, Gaudernack G (2005) Immunotherapy with allotumour mRNA-transfected dendritic cells in androgen-resistant prostate cancer patients. Br J Cancer 93:749–756

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  32. O’Neill DW, Adams S, Bhardwaj N (2004) Manipulating dendritic cell biology for the active immunotherapy of cancer. Blood 104:2235–2246

    Article  PubMed  CAS  Google Scholar 

  33. Pandha HS, John RJ, Hutchinson J, James N, Whelan M, Corbishley C, Dalgleish AG (2004) Dendritic cell immunotherapy for urological cancers using cryopreserved allogeneic tumour lysate-pulsed cells: a phase I/II study. BJU Int 94:412–418

    Article  PubMed  CAS  Google Scholar 

  34. Ribas A, Glaspy JA, Lee Y, Dissette VB, Seja E, Vu HT, Tchekmedyian NS, Oseguera D, Comin-Anduix B, Wargo JA, Amarnani SN, McBride WH, Economou JS, Butterfield LH (2004) Role of dendritic cell phenotype, determinant spreading, and negative costimulatory blockade in dendritic cell-based melanoma immunotherapy. J Immunother 27:354–367

    Article  PubMed  CAS  Google Scholar 

  35. Ribas A, Camacho LH, Lopez-Berestein G, Pavlov D, Bulanhagui CA, Millham R, Comin-Anduix B, Reuben JM, Seja E, Parker CA, Sharma A, Glaspy JA, Gomez-Navarro J (2005) Antitumour activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 23:8968–8977

    Article  PubMed  CAS  Google Scholar 

  36. Ricicova M, Palkova Z (2003) Comparative analyses of Saccharomyces cervesiae RNAs using Agilent RNA 6000 Nano Assay and agarose gel electrophoresis. FEMS Yeast Res 4:119–122

    Article  PubMed  CAS  Google Scholar 

  37. Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Restifo NP, Dudley ME, Schwarz SL, Spiess PJ, Wunderlich JR, Parkhurst MR, Kawakami Y, Seipp CA, Einhorn JH, White DE (1998) Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4:321–327

    Article  PubMed  CAS  Google Scholar 

  38. Saebøe-Larssen S, Fossberg E, Gaudernack G (2002) mRNA-based electrotransfection of human dendritic cells and induction of cytotoxic T lymphocyte responses against the telomerase catalytic subunit (hTERT). J Immunol Methods 259:191–203

    Article  PubMed  Google Scholar 

  39. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T (2001) Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumour immunity, and transplantation tolerance. Immunol Revi 182:18–32

    Article  CAS  Google Scholar 

  40. Salcedo M, Bercovici N, Taylor N, Vereecken P, Massicard S, Duriau D, Vernel-Pauillac F, Boyer A, Baron-Bodo V, Mallard E, Velu T (2005) Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumour cell lysate. Cancer Immunol Immunother 7:819–829

    Google Scholar 

  41. 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 tumour-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 

  42. Slingluff CL (1999) Targeting unique tumour antigens and modulating the cytokine environment may improve immunotherapy for tumours with immune escape mechanisms. Cancer Immunol Immunother 48:371–373

    Article  PubMed  CAS  Google Scholar 

  43. Speiser DE, Liénard D, Rufer N, Rubio-Godoy V, Rimoldi D, Lejeune F, Krieg AM, Cerottini JC, Romero P (2005) Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 115:739–746

    Article  PubMed  CAS  Google Scholar 

  44. Srivastava PK (1996) Do human cancers express shared protective antigens? or the necessity of remembrance of things past. Semin Immunol 8:295–302

    Article  PubMed  CAS  Google Scholar 

  45. Su Z, Dannull J, Heiser A, Yancey D, Pruitt S, Madden J, Coleman D, Niedzwiecki D, Gilboa E, Vieweg J (2003) Immunological and clinical responses in metastatic renal cancer patients vaccinated with tumour RNA-transfected dendritic cells. Cancer Res 63:2127–2133

    PubMed  CAS  Google Scholar 

  46. Su Z, Dannull J, Yang BK, Dahm P, Coleman D, Yancey D, Sichi S, Niedzwiecki D, Boczkowski D, Gilboa E, Vieweg J (2005) Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol 174:3798–3807

    PubMed  CAS  Google Scholar 

  47. 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 tumours. J Natl Cancer Inst 92:205–216

    Article  PubMed  CAS  Google Scholar 

  48. Vilella R, Benítez D, Milà J, Lozano M, Vilana R, Pomes J, Tomas X, Costa J, Vilalta A, Malvehy J, Puig S, Mellado B, Martí R, Castel T (2004) Pilot study of treatment of biochemotherapy-refractory stage IV melanoma patients with autologous dendritic cells pulsed with a heterologous melanoma cell line lysate. Cancer Immunol Immunother 53:651–658

    Article  PubMed  CAS  Google Scholar 

  49. Wierecky J, Mueller M, Brossart P (2006) Dendritic cell-based cancer immunotherapy targeting MUC-1. Cancer Immunol Immunother 55:63–67

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section for Immunotherapy, Department of Immunology, Cancer Research Institute, The Norwegian Radium Hospital, University of Oslo, 0310, Oslo, Norway

    Jon A. Kyte & Gustav Gaudernack

Authors
  1. Jon A. Kyte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gustav Gaudernack
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jon A. Kyte.

Additional information

This article is a symposium paper from the Annual Meeting of the “International Society for Cell and Gene Therapy of Cancer”, held in Shenzhen, China, on 9–11 December 2005.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kyte, J.A., Gaudernack, G. Immuno-gene therapy of cancer with tumour-mRNA transfected dendritic cells. Cancer Immunol Immunother 55, 1432–1442 (2006). https://doi.org/10.1007/s00262-006-0161-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-006-0161-7

Keywords

Search

Navigation