Top

Published in:

01-03-2015 | Original Article

Long-term clinical outcome of melanoma patients treated with messenger RNA-electroporated dendritic cell therapy following complete resection of metastases

Authors: Sofie Wilgenhof, Jurgen Corthals, An M. T. Van Nuffel, Daphné Benteyn, Carlo Heirman, Aude Bonehill, Kris Thielemans, Bart Neyns

Published in: Cancer Immunology, Immunotherapy | Issue 3/2015

Abstract

Purpose

Melanoma patients with a high risk of recurrence may benefit from immunotherapy with mRNA-electroporated autologous monocyte-derived dendritic cells (DCs). Further benefit may be found in combining DC-therapy with interferon alfa-2b.

Patients and methods

The long-term clinical outcome of AJCC stage III/IV melanoma patients who had no evidence of disease at the time of treatment with autologous mRNA-electroporated DCs in a single-center pilot clinical trial was analyzed. Antigen loading was accomplished by co-electroporation of mRNA encoding a fusion protein between MAGE-A1, -A3, -C2, Tyrosinase, MelanA/MART-1, or gp100, and an HLA class II-targeting sequence. DCs were administered by 4–6 bi-weekly intradermal injections. IFN-α-2b (5 MIU TIW) was initiated either at recurrence (cohort 1), concomitant with DCs (cohorts 2 and 3), or following the fourth DC administration (cohort 4).

Results

Thirty melanoma patients were recruited between April 2006 and June 2009. DC-related adverse events included grade 2 local injection site reactions in all patients, grade 2 fever and flu-like symptoms in one patient, and skin depigmentation in seven patients. After a median follow-up of over 6 years, the median relapse-free survival is 22 months (95 % CI 12–32 months). Twelve patients have died. The median overall survival has not been reached; the 2-year and 4-year survival rates are 93 and 70 %, respectively.

Conclusions

Adjuvant therapy following the resection of melanoma metastases with autologous mRNA-electroporated DCs, combined with interferon alfa-2b, is tolerable and results in encouraging long-term overall survival rates justifying further evaluation in a randomized clinical trial.

Balch CM, Gershenwald JE, Soong SJ et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199–6206CrossRefPubMedCentralPubMed

Eggermont AM, Suciu S, Testori A et al (2012) Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol 30:3810–3818CrossRefPubMed

Sondak VK, Kudchadkar R (2012) Pegylated interferon for the adjuvant treatment of melanoma: FDA approved, but what is its role? Oncologist 17:1223–1224CrossRefPubMedCentralPubMed

Mocellin S, Pasquali S, Rossi CR, Nitti D (2010) Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 102:493–501CrossRefPubMed

Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516CrossRefPubMedCentralPubMed

Hauschild A, Grob JJ, Demidov LV et al (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380:358–365CrossRefPubMed

Flaherty KT, Robert C, Hersey P et al (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367:107–114CrossRefPubMed

Hodi F, O’Day S, McDermott D et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723CrossRefPubMedCentralPubMed

Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526CrossRefPubMed

10.

Eggermont AM, Chiarion-Sileni V, Grob JJ et al (2014) Ipilimumab versus placebo after complete resection of stage III melanoma: initial efficacy and safety results from the EORTC 18071 phase III trial. ASCO Meeting Abstracts, Alexandria 32

11.

Boon T, Coulie P, Van den Eynde B, van der Bruggen P (2006) Human T cell responses against melanoma. Annu Rev Immunol 24:175–208CrossRefPubMed

12.

Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T (2014) Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer 14:135–146CrossRefPubMed

13.

Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12:265–277CrossRefPubMedCentralPubMed

14.

Connerotte T, Van Pel A, Godelaine D, Tartour E, Schuler-Thurner B, Lucas S, Thielemans K, Schuler G, Coulie P (2008) Functions of Anti-MAGE T-cells induced in melanoma patients under different vaccination modalities. Cancer Res 68:3931–3940CrossRefPubMed

15.

Bonehill A, Heirman C, Tuyaerts S, Michiels A, Breckpot K, Brasseur F, Zhang Y, Van Der Bruggen P, Thielemans K (2004) Messenger RNA-electroporated dendritic cells presenting MAGE-A3 simultaneously in HLA class I and class II molecules. J Immunol 172:6649–6657CrossRefPubMed

16.

Michiels A, Breckpot K, Corthals J, Tuyaerts S, Bonehill A, Heirman C, Thielemans K, Aerts JL (2006) Induction of antigen-specific CD8 + cytotoxic T cells by dendritic cells co-electroporated with a dsRNA analogue and tumor antigen mRNA. Gene Ther 13:1027–1036CrossRefPubMed

17.

Bonehill A, Tuyaerts S, Van Nuffel AM, Heirman C, Bos TJ, Fostier K, Neyns B, Thielemans K (2008) Enhancing the T-cell stimulatory capacity of human dendritic cells by co-electroporation with CD40L, CD70 and constitutively active TLR4 encoding mRNA. Mol Ther 16:1170–1180CrossRefPubMed

18.

Mitchell M, Jakowatz J, Harel W, Dean G, Stevenson L, Boswell W, Groshen S (1994) Increased effectiveness of interferon alfa-2b following active specific immunotherapy for melanoma. J Clin Oncol 12:402–411PubMed

19.

Astsaturov I, Petrella T, Bagriacik E et al (2003) Amplification of virus-induced antimelanoma T-cell reactivity by high-dose interferon-alpha2b: implications for cancer vaccines. Clin Cancer Res 9:4347–4355PubMed

20.

Di Pucchio T, Pilla L, Capone I et al (2006) Immunization of stage IV melanoma patients with Melan-A/MART-1 and gp100 peptides plus IFN-alpha results in the activation of specific CD8(+) T cells and monocyte/dendritic cell precursors. Cancer Res 66:4943–4951CrossRefPubMed

21.

Mitchell M, Abrams J, Thompson J et al (2007) Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon Alfa-2b compared with high-dose interferon Alfa-2b for Resected stage III cutaneous melanoma. J Clin Oncol 25:2078–2085CrossRefPubMed

22.

Kirkwood JM, Lee S, Moschos SJ, Albertini MR, Michalak JC, Sander C, Whiteside T, Butterfield LH, Weiner L (2009) Immunogenicity and antitumor effects of vaccination with peptide vaccine ± granulocyte–monocyte colony-stimulating factor and/or IFN-alpha2b in advanced metastatic melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696. Clin Cancer Res 15:1443–1451CrossRefPubMedCentralPubMed

23.

Schwartzentruber DJ, Lawson DH, Richards JM et al (2011) gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 364:2119–2127CrossRefPubMedCentralPubMed

24.

Yuan J, Gnjatic S, Li H et al (2008) CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit. Proc Natl Acad Sci USA 105:20410–20415CrossRefPubMedCentralPubMed

25.

Ribas A, Comin-Anduix B, Chmielowski B et al (2009) Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. Clin Cancer Res 15:6267–6276CrossRefPubMedCentralPubMed

26.

Wilgenhof S, Van Nuffel AM, Corthals J et al (2011) Therapeutic vaccination with an autologous mRNA electroporated dendritic cell vaccine in patients with advanced melanoma. J Immunother 34:448–456CrossRefPubMed

27.

Neyns B, Corthals J, De Greve J, De Greef C, Coulie PG, Thielemans K (2006) A cohort pilot study on therapeutic vaccination of advanced melanoma patients with dendritic cells loaded with multiple peptides or electroporated with mRNA. ASCO Meeting Abstracts 24: 18011

28.

Neyns B, Corthals J, Thielemans K (2007) Interferon alfa-2b treatment following therapeutic vaccination with mRNA electroporated dendritic cells results in skin depigmentation and tumor regression in patients with advanced melanoma. ASCO Meeting Abstracts 25: 8537

29.

Tuyaerts S, Noppe S, Corthals J, Breckpot K, Heirman C, De Greef C, Van Riet I, Thielemans K (2002) Generation of large numbers of dendritic cells in a closed system using cell factories. J Immunol Methods 264:135–151CrossRefPubMed

30.

Bonehill A, Van Nuffel A, Corthals J et al (2009) Single-step antigen loading and activation of dendritic cells by mRNA electroporation for the purpose of therapeutic vaccination in melanoma patients. Clin Cancer Res 15:3366–3375CrossRefPubMed

31.

Van Nuffel A, Corthals J, Neyns B, Heirman C, Thielemans K, Bonehill A (2010) Immunotherapy of cancer with dendritic cells loaded with tumor antigens and activated through mRNA electroporation. Methods Mol Biol 629:405–452PubMed

32.

Van Nuffel AM, Tuyaerts S, Benteyn D, Wilgenhof S, Corthals J, Heirman C, Neyns B, Thielemans K, Bonehill A (2012) Epitope and HLA-type independent monitoring of antigen-specific T-cells after treatment with dendritic cells presenting full-length tumor antigens. J Immunol Methods 377:23–36CrossRefPubMed

33.

Van Nuffel AM, Benteyn D, Wilgenhof S et al (2012) Dendritic cells loaded with mRNA encoding full-length tumor antigens prime CD4 + and CD8 + T cells in melanoma patients. Mol Ther 20:1063–1074CrossRefPubMedCentralPubMed

34.

Benteyn D, Van Nuffel AM, Wilgenhof S, Corthals J, Heirman C, Neyns B, Thielemans K, Bonehill A (2013) Characterization of CD8(+) T-cell responses in the peripheral blood and skin injection sites of melanoma patients treated with mRNA electroporated autologous dendritic cells (TriMixDC–MEL). Biomed Res Int 2013:976383CrossRefPubMedCentralPubMed

35.

Kantoff P, Higano C, Shore N et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422CrossRefPubMed

36.

Hasebe H, Nagayama H, Sato K, Enomoto M, Takeda Y, Takahashi TA, Hasumi K, Eriguchi M (2000) Dysfunctional regulation of the development of monocyte-derived dendritic cells in cancer patients. Biomed Pharmacother 54:291–298CrossRefPubMed

37.

Wolchok JD, Hoos A, O’Day S et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420CrossRefPubMed

38.

Van Nuffel AM, Benteyn D, Wilgenhof S, Corthals J, Heirman C, Neyns B, Thielemans K, Bonehill A (2012) Intravenous and intradermal TriMix-dendritic cell therapy results in a broad T-cell response and durable tumor response in a chemorefractory stage IV-M1c melanoma patient. Cancer Immunol Immunother 61:1033–1043CrossRefPubMed

39.

Wilgenhof S, Van Nuffel AM, Benteyn D et al (2013) A phase IB study on intravenous synthetic mRNA electroporated dendritic cell immunotherapy in pretreated advanced melanoma patients. Ann Oncol 24:2686–2693CrossRefPubMed

40.

Pectasides D, Dafni U, Bafaloukos D et al (2009) Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol 27:939–944CrossRefPubMed

Title: Long-term clinical outcome of melanoma patients treated with messenger RNA-electroporated dendritic cell therapy following complete resection of metastases
Authors: Sofie Wilgenhof
Jurgen Corthals
An M. T. Van Nuffel
Daphné Benteyn
Carlo Heirman
Aude Bonehill
Kris Thielemans
Bart Neyns
Publication date: 01-03-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 3/2015
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-014-1642-8

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

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Patients and methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2015

Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors

Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients

Glioblastoma exosomes and IGF-1R/AS-ODN are immunogenic stimuli in a translational research immunotherapy paradigm

Immunotherapies and novel combinations: the focus of advances in the treatment of melanoma

Expression and function of Toll-like receptors in peripheral blood mononuclear cells from patients with ovarian cancer

Association of high CD4-positive T cell infiltration with mutations in HLA class II-regulatory genes in microsatellite-unstable colorectal cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer