Skip to main content

Advertisement

SpringerLink
Log in

Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study

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

Abstract

Background and aims

Dendritic cell (DC)-based vaccination can induce antitumor T cell responses in vivo. This clinical pilot study examined feasibility and outcome of DC-based tumor vaccination for patients with advanced pancreatic adenocarcinoma.

Methods

Tumor lysate of patients with pancreatic carcinoma was generated by repeated freeze–thaw cycles of surgically obtained tissue specimens. Patients were eligible for DC vaccination after recurrence of pancreatic carcinoma or in a primarily palliative situation. DC were generated from peripheral blood mononuclear cells (PBMC), loaded with autologous tumor lysate, stimulated with TNF-α and PGE2 and injected intradermally. All patients received concomitant chemotherapy with gemcitabine. Disease response was the primary endpoint. Individual immunological responses to DC vaccination were analyzed by T cell-based immunoassays using pre- and post-vaccination samples of non-adherent PBMC.

Results

Twelve patients received DC vaccination and concomitant chemotherapy. One patient developed a partial remission, and two patients remained in stable disease. Median survival was 10.5 months. No severe side effects were observed. Tumor-reactive T cells could be detected prior to vaccination. DC vaccination increased the frequency of tumor-reactive cells in all patients tested; however, the degree of this increase varied. To quantify the presence of tumor-reactive T cells, stimulatory indices (SI) were calculated as the ratio of proliferation-inducing capacity of lysate-loaded versus -unloaded DC. The patient with longest overall survival of 56 months had a high SI of 6.49, indicating that the presence of a pre-vaccination antitumor T cell response might be associated with prolonged survival. Five patients survived 1 year or more.

Conclusion

DC-based vaccination can stimulate an antitumoral T cell response in patients with advanced or recurrent pancreatic carcinoma receiving concomitant gemcitabine treatment.

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
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

APC:

Antigen-presenting cells

DC:

Dendritic cells

DOC:

Died of other causes

DOD:

Dead of disease

DTH:

Delayed-type hypersensitivity

ELISPOT:

Enzyme-linked immunospot

KLH:

Keyhole limpet hemocyanin

PBMC:

Peripheral blood mononuclear cells

PMA:

Phorbol 12-myristate 13-acetate

SI:

Stimulatory index

TGF-β:

Transforming growth factor-β

References

  1. Ozols RF, Herbst RS, Colson YL, Gralow J, Bonner J, Curran WJ Jr, Eisenberg BL, Ganz PA, Kramer BS, Kris MG, Markman M, Mayer RJ, Raghavan D, Reaman GH, Sawaya R, Schilsky RL, Schuchter LM, Sweetenham JW, Vahdat LT, Winn RJ (2007) Clinical cancer advances 2006: Major research advances in cancer treatment, prevention, and screening–a report from the American society of clinical oncology. J Clin Oncol 25(1):146–162. doi:10.1200/JCO.2006.09.7030

    Article  PubMed  CAS  Google Scholar 

  2. Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15(6):2403–2413

    PubMed  CAS  Google Scholar 

  3. Rothenberg ML, Moore MJ, Cripps MC, Andersen JS, Portenoy RK, Burris HA 3rd, Green MR, Tarassoff PG, Brown TD, Casper ES, Storniolo AM, Von Hoff DD (1996) A phase ii trial of gemcitabine in patients with 5-fu-refractory pancreas cancer. Ann Oncol 7(4):347–353

    PubMed  CAS  Google Scholar 

  4. Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, Zaniboni A, Ducreux M, Aitini E, Taieb J, Faroux R, Lepere C, de Gramont A (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a gercor and giscad phase iii trial. J Clin Oncol 23(15):3509. doi:10.1200/JCO.2005.06.023

    Article  PubMed  CAS  Google Scholar 

  5. Dauer M, Schnurr M, Eigler A (2008) Dendritic cell-based cancer vaccination: Quo vadis? Expert Rev Vaccines 7(7):1041–1053. doi:10.1586/14760584.7.7.1041

    Article  PubMed  CAS  Google Scholar 

  6. Kantoff PW, Higano CS, Shore NDE, Berger R, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF (2010) Sipuleucel-t immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422

    Article  PubMed  CAS  Google Scholar 

  7. Steinman RM, Banchereau J (2007) Taking dendritic cells into medicine. Nature 449(7161):419–426. doi:10.1038/nature06175

    Article  PubMed  CAS  Google Scholar 

  8. Chaux P, Favre N, Martin M, Martin F (1997) Tumor-infiltrating dendritic cells are defective in their antigen-presenting function and inducible b7 expression in rats. Int J Cancer 72(4):619–624. doi:10.1002/(SICI)1097-0215(19970807)72:4<619:AID-IJC12>3.0.CO;2-6

    Article  PubMed  CAS  Google Scholar 

  9. Troy AJ, Summers KL, Davidson PJ, Atkinson CH, Hart DN (1998) Minimal recruitment and activation of dendritic cells within renal cell carcinoma. Clin Cancer Res 4(3):585–593

    PubMed  CAS  Google Scholar 

  10. Dauer M, Lam V, Arnold H, Junkmann J, Kiefl R, Bauer C, Schnurr M, Endres S, Eigler A (2008) Combined use of toll-like receptor agonists and prostaglandin e(2) in the fastdc model: Rapid generation of human monocyte-derived dendritic cells capable of migration and il-12p70 production. J Immunol Methods 337(2):97–105. doi:10.1016/j.jim.2008.07.003

    Article  PubMed  CAS  Google Scholar 

  11. Dauer M, Obermaier B, Herten J, Haerle C, Pohl K, Rothenfusser S, Schnurr M, Endres S, Eigler A (2003) Mature dendritic cells derived from human monocytes within 48 h: a novel strategy for dendritic cell differentiation from blood precursors. J Immunol 170(8):4069–4076

    PubMed  CAS  Google Scholar 

  12. Schnurr M, Galambos P, Scholz C, Then F, Dauer M, Endres S, Eigler A (2001) Tumor cell lysate-pulsed human dendritic cells induce a t-cell response against pancreatic carcinoma cells: An in vitro model for the assessment of tumor vaccines. Cancer Res 61(17):6445–6450

    PubMed  CAS  Google Scholar 

  13. Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G (2008) Immunological aspects of cancer chemotherapy. Nat Rev Immunol 8(1):59–73. doi:10.1038/nri2216

    Article  PubMed  CAS  Google Scholar 

  14. Suzuki E, Kapoor V, Jassar AS, Kaiser LR, Albelda SM (2005) Gemcitabine selectively eliminates splenic gr-1 +/cd11b + myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 11(18):6713–6721. doi:10.1158/1078-0432.CCR-05-0883

    Article  PubMed  CAS  Google Scholar 

  15. Nowak AK, Lake RA, Marzo AL, Scott B, Heath WR, Collins EJ, Frelinger JA, Robinson BW (2003) Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific cd8 t cells. J Immunol 170(10):4905–4913

    PubMed  CAS  Google Scholar 

  16. Dauer M, Herten J, Bauer C, Renner F, Schad K, Schnurr M, Endres S, Eigler A (2005) Chemosensitization of pancreatic carcinoma cells to enhance t cell-mediated cytotoxicity induced by tumor lysate-pulsed dendritic cells. J Immunother 28(4):332–342

    Article  PubMed  Google Scholar 

  17. Bauer C, Bauernfeind F, Sterzik A, Orban M, Schnurr M, Lehr HA, Endres S, Eigler A, Dauer M (2007) Dendritic cell-based vaccination combined with gemcitabine increases survival in a murine pancreatic carcinoma model. Gut 56(9):1275–1282. doi:10.1136/gut.2006.108621

    Article  PubMed  CAS  Google Scholar 

  18. Hirooka Y, Itoh A, Kawashima H, Hara K, Nonogaki K, Kasugai T, Ohno E, Ishikawa T, Matsubara H, Ishigami M, Katano Y, Ohmiya N, Niwa Y, Yamamoto K, Kaneko T, Nieda M, Yokokawa K, Goto H (2009) A combination therapy of gemcitabine with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Pancreas 38(3):e69–e74. doi:10.1097/MPA.0b013e318197a9e3

    Article  PubMed  CAS  Google Scholar 

  19. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: Revised recist guideline (version 1.1). Eur J Cancer 45(2):228–247. doi:10.1016/j.ejca.2008.10.026

    Article  PubMed  CAS  Google Scholar 

  20. Heinemann V, Boeck S, Hinke A, Labianca R, Louvet C (2008) Meta-analysis of randomized trials: Evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8(1):82. doi:10.1186/1471-2407-8-82

    Article  PubMed  Google Scholar 

  21. Carpelan-Holmstrom M, Nordling S, Pukkala E, Sankila R, Luttges J, Kloppel G, Haglund C (2005) Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the finnish cancer registry. Gut 54(3):385–387. doi:10.1136/gut.2004.047191

    Article  PubMed  CAS  Google Scholar 

  22. Holen KD, Klimstra DS, Hummer A, Gonen M, Conlon K, Brennan M, Saltz LB (2002) Clinical characteristics and outcomes from an institutional series of acinar cell carcinoma of the pancreas and related tumors. J Clin Oncol 20(24):4673–4678

    Article  PubMed  Google Scholar 

  23. Butturini G, Pisano M, Scarpa A, D’Onofrio M, Auriemma A, Bassi C Aggressive approach to acinar cell carcinoma of the pancreas: A single-institution experience and a literature review. Langenbecks Arch Surg. doi:10.1007/s00423-010-0706-2

  24. Kubuschok B, Xie X, Jesnowski R, Preuss KD, Romeike BF, Neumann F, Regitz E, Pistorius G, Schilling M, Scheunemann P, Izbicki JR, Lohr JM, Pfreundschuh M (2004) Expression of cancer testis antigens in pancreatic carcinoma cell lines, pancreatic adenocarcinoma and chronic pancreatitis. Int J Cancer 109(4):568–575. doi:10.1002/ijc.20006

    Article  PubMed  CAS  Google Scholar 

  25. Menard C, Martin F, Apetoh L, Bouyer F, Ghiringhelli F (2008) Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol Immunother 57(11):1579–1587. doi:10.1007/s00262-008-0505-6

    Article  PubMed  CAS  Google Scholar 

  26. Gulley JL, Madan RA, Arlen PM (2007) Enhancing efficacy of therapeutic vaccinations by combination with other modalities. Vaccine 25(Suppl 2):B89–B96. doi:10.1016/j.vaccine.2007.04.091

    Article  PubMed  CAS  Google Scholar 

  27. von Bernstorff W, Voss M, Freichel S, Schmid A, Vogel I, Johnk C, Henne-Bruns D, Kremer B, Kalthoff H (2001) Systemic and local immunosuppression in pancreatic cancer patients. Clin Cancer Res 7(3 Suppl):925s–932s

    Google Scholar 

  28. Hiraoka N, Onozato K, Kosuge T, Hirohashi S (2006) Prevalence of foxp3 + regulatory t cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12(18):5423–5434. doi:10.1158/1078-0432.CCR-06-0369

    Article  PubMed  CAS  Google Scholar 

  29. Lin Y, Kikuchi S, Tamakoshi A, Obata Y, Yagyu K, Inaba Y, Kurosawa M, Kawamura T, Motohashi Y, Ishibashi T (2006) Serum transforming growth factor-beta1 levels and pancreatic cancer risk: A nested case-control study (japan). Cancer Causes Control 17(8):1077–1082. doi:10.1007/s10552-006-0048-0

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Gravenhorst Stiftung (M.D.), the Förderprogramm für Forschung und Lehre (FöFoLe) of the University of Munich (C.B.), the Deutsche Forschungsgemeinschaft (Ba 3824/1-1 to C.B. and Graduiertenkolleg 1202 to M.S., S.E.), and the Deutsche Krebshilfe (M.S.). This work is part of the doctoral thesis of S.S. at the University of Munich.

Conflict of interest

All authors declare that no conflicts of interest exist.

Author information

Authors and Affiliations

  1. Medizinische Klinik Innenstadt, University of Munich, München, Germany

    Christian Bauer, Samira Saraj, Maximilian Schnurr, Franz Bauernfeind, Alexander Sterzik, Jana Junkmann, Veronika Jakl, Rosemarie Kiefl, Fuat Oduncu, Bertold Emmerich & Andreas Eigler

  2. Division of Clinical Pharmacology, Medizinische Klinik Innenstadt, University of Munich, München, Germany

    Stefan Endres

  3. Chirurgische Klinik und Poliklinik Großhadern, University of Munich, München, Germany

    Christiane Bruns, Dominik Rüttinger, Claudius Conrad & Karl-Walter Jauch

  4. Chirurgische Klinik und Poliklinik Innenstadt, University of Munich, München, Germany

    Thomas Mussack

  5. Department of Medicine II, Saarland University Hospital, Saarland University, Homburg/Saar, Germany

    Marc Dauer

  6. Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Claudius Conrad

  7. Pathologisches Institut, University of Munich, München, Germany

    Doris Mayr

  8. Department of Internal Medicine I, Klinikum Dritter Orden, Teaching Hospital, University of Munich, Menzinger Strasse 44, 80638, München, Germany

    Andreas Eigler

Authors
  1. Christian Bauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marc Dauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samira Saraj
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maximilian Schnurr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Franz Bauernfeind
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alexander Sterzik
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jana Junkmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Veronika Jakl
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Rosemarie Kiefl
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fuat Oduncu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Bertold Emmerich
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Doris Mayr
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Thomas Mussack
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Christiane Bruns
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Dominik Rüttinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Claudius Conrad
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Karl-Walter Jauch
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Stefan Endres
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Andreas Eigler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andreas Eigler.

Additional information

C. Bauer and M. Dauer both authors have contributed equally.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 2080 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bauer, C., Dauer, M., Saraj, S. et al. Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study. Cancer Immunol Immunother 60, 1097–1107 (2011). https://doi.org/10.1007/s00262-011-1023-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-011-1023-5

Keywords

Search

Navigation