Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 10/2012

01-10-2012 | Original article

Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial

Authors: Eva Ellebaek, Lotte Engell-Noerregaard, Trine Zeeberg Iversen, Thomas Moerch Froesig, Shamaila Munir, Sine Reker Hadrup, Mads Hald Andersen, Inge Marie Svane

Published in: Cancer Immunology, Immunotherapy | Issue 10/2012

Login to get access

Abstract

Dendritic cells (DC) are the most potent antigen presenting cells and have proven effective in stimulation of specific immune responses in vivo. Competing immune inhibition could limit the clinical efficacy of DC vaccination. In this phase II trial, metronomic Cyclophosphamide and a Cox-2 inhibitor have been added to a DC vaccine with the intend to dampen immunosuppressive mechanisms. Twenty-eight patients with progressive metastatic melanoma were treated with autologous DCs pulsed with survivin, hTERT, and p53-derived peptides (HLA-A2+) or tumor lysate (HLA-A2−). Concomitantly the patients were treated with IL-2, Cyclophosphamide, and Celecoxib. The treatment was safe and tolerable. Sixteen patients (57 %) achieved stable disease (SD) at 1st evaluation and 8 patients had prolonged SD (7–13.7 months). The median OS was 9.4 months. Patients with SD had an OS of 10.5 months while patients with progressive disease (PD) had an OS of 6.0 months (p = 0.048) even though there were no differences in prognostic factors between the two groups. Despite the use of metronomic Cyclophosphamide, regulatory T cells did not decrease during treatment. Indirect IFN-γ ELISPOT assays showed a general increase in immune responses from baseline to the time of 4th vaccination. Induction of antigen-specific immune responses was seen in 9 out of 15 screened HLA-A2+ patients. In conclusion, the number of patients obtaining SD more than doubled and 6-month survival significantly increased compared to a previous trial without Cyclophosphamide and Celecoxib. A general increase in immune responses against the tested peptides was observed.
Appendix
Available only for authorised users
Literature
1.
Lee ML, Tomsu K, Von Eschen KB (2000) Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res 10:81–92PubMed
2.
Agarwala SS (2009) Current systemic therapy for metastatic melanoma. Expert Rev Anticancer Ther 9:587–595PubMedCrossRef
3.
Quirt I, Verma S, Petrella T, Bak K, Charette M (2007) Temozolomide for the treatment of metastatic melanoma: a systematic review. Oncologist 12:1114–1123PubMedCrossRef
4.
Anderson CM, Buzaid AC, Legha SS (1995) Systemic treatments for advanced cutaneous melanoma. Oncology (Williston Park) 9:1149–1158
5.
Dutcher J (2002) Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma. Oncology (Williston Park) 16:4–10
6.
Gajewski TF (2010) Improved melanoma survival at last! Ipilimumab and a paradigm shift for immunotherapy. Pigment Cell Melanoma Res 23:580–581PubMedCrossRef
7.
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723PubMedCrossRef
8.
9.
Osada T, Clay TM, Woo CY, Morse MA, Lyerly HK (2006) Dendritic cell-based immunotherapy. Int Rev Immunol 25:377–413PubMedCrossRef
10.
11.
Gabrilovich DI, Nagaraj S (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 9:162–174PubMedCrossRef
12.
Ahmadzadeh M, Rosenberg SA (2006) IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood 107:2409–2414PubMedCrossRef
13.
Berntsen A, Trepiakas R, Wenandy L, Geertsen PF, Thor SP, Andersen MH et al (2008) Therapeutic dendritic cell vaccination of patients with metastatic renal cell carcinoma: a clinical phase 1/2 trial. J Immunother 31:771–780PubMedCrossRef
14.
Trepiakas R, Berntsen A, Hadrup SR, Bjorn J, Geertsen PF, Straten PT et al (2010) Vaccination with autologous dendritic cells pulsed with multiple tumor antigens for treatment of patients with malignant melanoma: results from a phase I/II trial. Cytotherapy 12:721–734PubMedCrossRef
15.
16.
Jacobs JF, Punt CJ, Lesterhuis WJ, Sutmuller RP, Brouwer HM, Scharenborg NM et al (2010) Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin Cancer Res 16:5067–5078PubMedCrossRef
17.
Nishikawa H, Sakaguchi S (2010) Regulatory T cells in tumor immunity. Int J Cancer 127:759–767PubMed
18.
Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F et al (2007) Metronomic cyclophosphamide regimen selectively depletes CD4+ CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother 56:641–648PubMedCrossRef
19.
Liu JY, Wu Y, Zhang XS, Yang JL, Li HL, Mao YQ et al (2007) Single administration of low dose cyclophosphamide augments the antitumor effect of dendritic cell vaccine. Cancer Immunol Immunother 56:1597–1604PubMedCrossRef
20.
Lutsiak ME, Semnani RT, De PR, Kashmiri SV, Schlom J, Sabzevari H (2005) Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105:2862–2868PubMedCrossRef
21.
Denkert C, Kobel M, Berger S, Siegert A, Leclere A, Trefzer U et al (2001) Expression of cyclooxygenase 2 in human malignant melanoma. Cancer Res 61:303–308PubMed
22.
Goulet AC, Einsphar JG, Alberts DS, Beas A, Burk C, Bhattacharyya A et al (2003) Analysis of cyclooxygenase 2 (COX-2) expression during malignant melanoma progression. Cancer Biol Ther 2:713–718PubMed
23.
Becker MR, Siegelin MD, Rompel R, Enk AH, Gaiser T (2009) COX-2 expression in malignant melanoma: a novel prognostic marker? Melanoma Res 19:8–16PubMedCrossRef
24.
Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside TL (2007) Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. Cancer Res 67:8865–8873PubMedCrossRef
25.
Mahic M, Yaqub S, Johansson CC, Tasken K, Aandahl EM (2006) FOXP3+ CD4+ CD25+ adaptive regulatory T cells express cyclooxygenase-2 and suppress effector T cells by a prostaglandin E2-dependent mechanism. J Immunol 177:246–254PubMed
26.
Sharma S, Yang SC, Zhu L, Reckamp K, Gardner B, Baratelli F et al (2005) Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer. Cancer Res 65:5211–5220PubMedCrossRef
27.
Sinha P, Clements VK, Fulton AM, Ostrand-Rosenberg S (2007) Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells. Cancer Res 67:4507–4513PubMedCrossRef
28.
Toebes M, Coccoris M, Bins A, Rodenko B, Gomez R, Nieuwkoop NJ et al (2006) Design and use of conditional MHC class I ligands. Nat Med 12:246–251PubMedCrossRef
29.
Hadrup SR, Bakker AH, Shu CJ, Andersen RS, van VJ, Hombrink P et al (2009) Parallel detection of antigen-specific T-cell responses by multidimensional encoding of MHC multimers. Nat Methods 6:520–526PubMedCrossRef
30.
Andersen MH, Pedersen LO, Becker JC, Straten PT (2001) Identification of a cytotoxic T lymphocyte response to the apoptosis inhibitor protein survivin in cancer patients. Cancer Res 61:869–872PubMed
31.
McCutcheon M, Wehner N, Wensky A, Kushner M, Doan S, Hsiao L et al (1997) A sensitive ELISPOT assay to detect low-frequency human T lymphocytes. J Immunol Methods 210:149–166PubMedCrossRef
32.
Poschke I, Mougiakakos D, Hansson J, Masucci GV, Kiessling R (2010) Immature immunosuppressive CD14 + HLA-DR-/low cells in melanoma patients are Stat3hi and overexpress CD80, CD83, and DC-sign. Cancer Res 70:4335–4345PubMedCrossRef
33.
Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ (2004) Dendritic cell immunotherapy: mapping the way. Nat Med 10:475–480PubMedCrossRef
34.
Manola J, Atkins M, Ibrahim J, Kirkwood J (2000) Prognostic factors in metastatic melanoma: a pooled analysis of Eastern cooperative oncology group trials. J Clin Oncol 18:3782–3793PubMed
35.
36.
Svane IM, Pedersen AE, Johnsen HE, Nielsen D, Kamby C, Gaarsdal E et al (2004) Vaccination with p53-peptide-pulsed dendritic cells, of patients with advanced breast cancer: report from a phase I study. Cancer Immunol Immunother 53:633–641PubMedCrossRef
37.
Schrama D, Pedersen LO, Keikavoussi P, Andersen MH, Straten Pt, Brocker EB et al (2002) Aggregation of antigen-specific T cells at the inoculation site of mature dendritic cells. J Invest Dermatol 119:1443–1448PubMedCrossRef
38.
Lopez MN, Pereda C, Segal G, Munoz L, Aguilera R, Gonzalez FE et al (2009) Prolonged survival of dendritic cell-vaccinated melanoma patients correlates with tumor-specific delayed type IV hypersensitivity response and reduction of tumor growth factor beta-expressing T cells. J Clin Oncol 27:945–952PubMedCrossRef
39.
Ridolfi L, Petrini M, Fiammenghi L, Granato AM, Ancarani V, Pancisi E et al (2010) Unexpected high response rate to traditional therapy after dendritic cell-based vaccine in advanced melanoma: update of clinical outcome and subgroup analysis. Clin Dev Immunol 2010:504979PubMedCrossRef
40.
Ridolfi L, Petrini M, Fiammenghi L, Granato AM, Ancarani V, Pancisi E et al (2011) Dendritic cell-based vaccine in advanced melanoma: update of clinical outcome. Melanoma Res 21:524–529PubMedCrossRef
41.
Engell-Noerregaard L, Hansen TH, Andersen MH, Thor SP, Svane IM (2009) Review of clinical studies on dendritic cell-based vaccination of patients with malignant melanoma: assessment of correlation between clinical response and vaccine parameters. Cancer Immunol Immunother 58:1–14PubMedCrossRef
42.
Hersey P, Halliday G, Farrelly M, DeSilva C, Lett M, Menzies S (2008) Phase I/II study of treatment with matured dendritic cells with or without low dose IL-2 in patients with disseminated melanoma. Cancer Immunol Immunother 57:1039–1051PubMedCrossRef
43.
Andersen MH, Gehl J, Reker S, Pedersen LO, Becker JC, Geertsen P et al (2003) Dynamic changes of specific T cell responses to melanoma correlate with IL-2 administration. Semin Cancer Biol 13:449–459PubMedCrossRef
44.
Iniguez MA, Punzon C, Fresno M (1999) Induction of cyclooxygenase-2 on activated T lymphocytes: regulation of T cell activation by cyclooxygenase-2 inhibitors. J Immunol 163:111–119PubMed
45.
Paccani SR, Boncristiano M, Ulivieri C, D’Elios MM, Del PG, Baldari CT (2002) Nonsteroidal anti-inflammatory drugs suppress T-cell activation by inhibiting p38 MAPK induction. J Biol Chem 277:1509–1513PubMedCrossRef
46.
Pettersen FO, Torheim EA, Dahm AE, Aaberge IS, Lind A, Holm M et al (2011) An exploratory trial of cyclooxygenase type 2 inhibitor in HIV-1 infection: downregulated immune activation and improved T cell-dependent vaccine responses. J Virol 85:6557–6566PubMedCrossRef
47.
Kleinewietfeld M, Starke M, Di MD, Borsellino G, Battistini L, Rotzschke O et al (2009) CD49d provides access to “untouched” human Foxp3 + Treg free of contaminating effector cells. Blood 113:827–836PubMedCrossRef
48.
Solito S, Falisi E, Diaz-Montero CM, Doni A, Pinton L, Rosato A et al (2011) A human promyelocytic-like population is responsible for the immune suppression mediated by myeloid-derived suppressor cells. Blood 118:2254–2265PubMedCrossRef
49.
Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49–59PubMedCrossRef
50.
51.
Finkelstein SE, Carey T, Fricke I, Yu D, Goetz D, Gratz M et al (2010) Changes in dendritic cell phenotype after a new high-dose weekly schedule of interleukin-2 therapy for kidney cancer and melanoma. J Immunother 33:817–827PubMedCrossRef
52.
Mirza N, Fishman M, Fricke I, Dunn M, Neuger AM, Frost TJ et al (2006) All-trans-retinoic acid improves differentiation of myeloid cells and immune response in cancer patients. Cancer Res 66:9299–9307PubMedCrossRef
53.
de Vries IJ, Lesterhuis WJ, Scharenborg NM, Engelen LP, Ruiter DJ, Gerritsen MJ et al (2003) Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. Clin Cancer Res 9:5091–5100PubMed
54.
Wadler S, Einzig AI, Dutcher JP, Ciobanu N, Landau L, Wiernik PH (1988) Phase II trial of recombinant alpha-2b-interferon and low-dose cyclophosphamide in advanced melanoma and renal cell carcinoma. Am J Clin Oncol 11:55–59PubMedCrossRef
55.
Lindemann A, Hoffken K, Schmidt RE, Diehl V, Kloke O, Gamm H et al (1989) A phase-II study of low-dose cyclophosphamide and recombinant human interleukin-2 in metastatic renal cell carcinoma and malignant melanoma. Cancer Immunol Immunother 28:275–281PubMedCrossRef
56.
Eggermont AM, Kirkwood JM (2004) Re-evaluating the role of dacarbazine in metastatic melanoma: what have we learned in 30 years? Eur J Cancer 40:1825–1836PubMedCrossRef
57.
Jilaveanu LB, Aziz SA, Kluger HM (2009) Chemotherapy and biologic therapies for melanoma: do they work? Clin Dermatol 27:614–625PubMedCrossRef
58.
Powell DJ Jr, de Vries CR, Allen T, Ahmadzadeh M, Rosenberg SA (2007) Inability to mediate prolonged reduction of regulatory T Cells after transfer of autologous CD25-depleted PBMC and interleukin-2 after lymphodepleting chemotherapy. J Immunother 30:438–447PubMedCrossRef
59.
60.
Shaked Y, Emmenegger U, Man S, Cervi D, Bertolini F, Ben-David Y et al (2005) Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106:3058–3061PubMedCrossRef
61.
Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O’Reilly MS et al (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886PubMed
Metadata
Title
Metastatic melanoma patients treated with dendritic cell vaccination, Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial
Authors
Eva Ellebaek
Lotte Engell-Noerregaard
Trine Zeeberg Iversen
Thomas Moerch Froesig
Shamaila Munir
Sine Reker Hadrup
Mads Hald Andersen
Inge Marie Svane
Publication date
01-10-2012
Publisher
Springer-Verlag
Published in
Cancer Immunology, Immunotherapy / Issue 10/2012
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-012-1242-4

Other articles of this Issue 10/2012

Cancer Immunology, Immunotherapy 10/2012 Go to the issue

Original article

Cancerous HLA class I expression and regulatory T cell infiltration in gastric cancer

Original article

Tumor-associated myeloid cells can be activated in vitro and in vivo to mediate antitumor effects

Original article

Hodgkin’s lymphoma RNA-transfected dendritic cells induce cancer/testis antigen-specific immune responses

Review

Endothelial cells in the eyes of an immunologist

Original article

CA215 and GnRH receptor as targets for cancer therapy

Original article

Induction on differentiation and modulation of bone marrow progenitor of dendritic cell by methionine enkephalin (MENK)
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits