Dendritic cell-based vaccination of patients with advanced pancreatic carcinoma: results of a pilot study
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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.
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.
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.
DC-based vaccination can stimulate an antitumoral T cell response in patients with advanced or recurrent pancreatic carcinoma receiving concomitant gemcitabine treatment.
KeywordsImmunotherapy Pancreatic cancer Dendritic cell Vaccination
Died of other causes
Dead of disease
Keyhole limpet hemocyanin
Peripheral blood mononuclear cells
Phorbol 12-myristate 13-acetate
Transforming growth factor-β
- 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.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
- 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
- 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
- 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
- 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.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
- 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.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
- 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 PubMedCrossRefGoogle 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–932sGoogle 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 PubMedCrossRefGoogle Scholar