Cancer Immunology, Immunotherapy

, Volume 60, Issue 8, pp 1097–1107 | Cite as

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

  • Christian Bauer
  • Marc Dauer
  • Samira Saraj
  • Maximilian Schnurr
  • Franz Bauernfeind
  • Alexander Sterzik
  • Jana Junkmann
  • Veronika Jakl
  • Rosemarie Kiefl
  • Fuat Oduncu
  • Bertold Emmerich
  • Doris Mayr
  • Thomas Mussack
  • Christiane Bruns
  • Dominik Rüttinger
  • Claudius Conrad
  • Karl-Walter Jauch
  • Stefan Endres
  • Andreas Eigler
Original article

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.

Keywords

Immunotherapy Pancreatic cancer Dendritic cell Vaccination 

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

Supplementary material

262_2011_1023_MOESM1_ESM.pdf (2 mb)
Supplementary material 1 (PDF 2080 kb)

References

  1. 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 PubMedCrossRefGoogle Scholar
  2. 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):2403–2413PubMedGoogle Scholar
  3. 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):347–353PubMedGoogle Scholar
  4. 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 PubMedCrossRefGoogle Scholar
  5. 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 PubMedCrossRefGoogle Scholar
  6. 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 363:411–422PubMedCrossRefGoogle Scholar
  7. 7.
    Steinman RM, Banchereau J (2007) Taking dendritic cells into medicine. Nature 449(7161):419–426. doi:10.1038/nature06175 PubMedCrossRefGoogle Scholar
  8. 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 PubMedCrossRefGoogle Scholar
  9. 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):585–593PubMedGoogle Scholar
  10. 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 PubMedCrossRefGoogle Scholar
  11. 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):4069–4076PubMedGoogle Scholar
  12. 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):6445–6450PubMedGoogle Scholar
  13. 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 PubMedCrossRefGoogle Scholar
  14. 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 PubMedCrossRefGoogle Scholar
  15. 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):4905–4913PubMedGoogle Scholar
  16. 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):332–342PubMedCrossRefGoogle Scholar
  17. 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 PubMedCrossRefGoogle Scholar
  18. 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 PubMedCrossRefGoogle Scholar
  19. 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 PubMedCrossRefGoogle Scholar
  20. 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 PubMedCrossRefGoogle Scholar
  21. 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 PubMedCrossRefGoogle Scholar
  22. 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):4673–4678PubMedCrossRefGoogle Scholar
  23. 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. 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 PubMedCrossRefGoogle Scholar
  25. 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 PubMedCrossRefGoogle Scholar
  26. 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 PubMedCrossRefGoogle Scholar
  27. 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–932sGoogle Scholar
  28. 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 PubMedCrossRefGoogle Scholar
  29. 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 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Christian Bauer
    • 1
  • Marc Dauer
    • 5
  • Samira Saraj
    • 1
  • Maximilian Schnurr
    • 1
  • Franz Bauernfeind
    • 1
  • Alexander Sterzik
    • 1
  • Jana Junkmann
    • 1
  • Veronika Jakl
    • 1
  • Rosemarie Kiefl
    • 1
  • Fuat Oduncu
    • 1
  • Bertold Emmerich
    • 1
  • Doris Mayr
    • 7
  • Thomas Mussack
    • 4
  • Christiane Bruns
    • 3
  • Dominik Rüttinger
    • 3
  • Claudius Conrad
    • 3
    • 6
  • Karl-Walter Jauch
    • 3
  • Stefan Endres
    • 2
  • Andreas Eigler
    • 1
    • 8
  1. 1.Medizinische Klinik InnenstadtUniversity of MunichMünchenGermany
  2. 2.Division of Clinical Pharmacology, Medizinische Klinik InnenstadtUniversity of MunichMünchenGermany
  3. 3.Chirurgische Klinik und Poliklinik GroßhadernUniversity of MunichMünchenGermany
  4. 4.Chirurgische Klinik und Poliklinik InnenstadtUniversity of MunichMünchenGermany
  5. 5.Department of Medicine IISaarland University Hospital, Saarland UniversityHomburg/SaarGermany
  6. 6.Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  7. 7.Pathologisches InstitutUniversity of MunichMünchenGermany
  8. 8.Department of Internal Medicine I, Klinikum Dritter Orden, Teaching HospitalUniversity of MunichMünchenGermany

Personalised recommendations