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

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

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Abbreviations

18F-FDG:

18F-fluorodeoxyglucose

AEs:

Adverse events

AJCC:

American Joint Committee on Cancer

caTLR4:

Constitutively active Toll-like receptor 4

CD40L:

CD40 ligand

CI:

Confidence interval

CTLA-4:

Cytotoxic T-lymphocyte-associated antigen 4

CT:

Computed tomography

DC:

Dendritic cell

DTH:

Delayed-type hypersensitivity

GM-CSF:

Granulocyte/macrophage colony-stimulating factor

HLA:

Human leucocyte antigen

IL-2:

Interleukin-2

IL-4:

Interleukin-4

IFN-α-2b:

Interferon alfa-2b

LDH:

Lactate dehydrogenase

MAAs:

Melanoma-associated antigens

MAPK:

Mitogen-activated protein kinase

MIU:

Million international units

MRI:

Magnetic resonance imaging

mRNA:

Messenger ribonucleic acid

OS:

Overall survival

PET–CT:

Positron emission tomography–computed tomography

RFS:

Relapse-free survival

SKILs:

Skin infiltrating lymphocytes

Th1:

T helper type 1

TIW:

Three times in a week

WHO-PS:

World Health Organization Performance Status

References

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

    Article  PubMed Central  PubMed  Google Scholar 

  2. 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 30:3810–3818

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. 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 102:493–501

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. 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 380:358–365

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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 14:135–146

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 68:3931–3940

    Article  CAS  PubMed  Google Scholar 

  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 172:6649–6657

    Article  CAS  PubMed  Google Scholar 

  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 13:1027–1036

    Article  CAS  PubMed  Google Scholar 

  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 16:1170–1180

    Article  CAS  PubMed  Google Scholar 

  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 12:402–411

    CAS  PubMed  Google Scholar 

  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 9:4347–4355

    CAS  PubMed  Google Scholar 

  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 66:4943–4951

    Article  PubMed  Google Scholar 

  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 25:2078–2085

    Article  CAS  PubMed  Google Scholar 

  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 15:1443–1451

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 364:2119–2127

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 105:20410–20415

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 15:6267–6276

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  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 34:448–456

    Article  CAS  PubMed  Google Scholar 

  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 264:135–151

    Article  CAS  PubMed  Google Scholar 

  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 15:3366–3375

    Article  CAS  PubMed  Google Scholar 

  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 629:405–452

    PubMed  Google Scholar 

  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 377:23–36

    Article  PubMed  Google Scholar 

  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 20:1063–1074

    Article  PubMed Central  PubMed  Google Scholar 

  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 2013:976383

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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 54:291–298

    Article  CAS  PubMed  Google Scholar 

  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 15:7412–7420

    Article  CAS  PubMed  Google Scholar 

  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 61:1033–1043

    Article  PubMed  Google Scholar 

  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 24:2686–2693

    Article  CAS  PubMed  Google Scholar 

  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 27:939–944

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the patients who consented to participate in the clinical study, their families, and referring physicians. We are very much indebted to the data managers Katrien Van den Bossche and Kathleen Mooren, and to Elsy Vaeremans, Gwenny De Metter, Inge Betz, Chiraz Mahmoud for excellent technical assistance, and to Prof. Coomans for help with the statistical analyses. This work was supported by grants from the Interuniversity Attraction Poles Program—Belgian State—Belgian Science Policy, the Stichting tegen Kanker, an Integrated Project and a Network of Excellence sponsored by the EU, the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO-Vlaanderen) and the Willy Gepts Wetenschappelijk Fonds of the Universitair Ziekenhuis Brussel. Sofie Wilgenhof is a PhD student of the FWO-Vlaanderen.

Conflict of interest

The use of dendritic cells electroporated with tumor antigen mRNA and TriMix is the topic of a patent (W2009/034172) on which Dr. A. Bonehill and Prof. Dr. K. Thielemans are filed as inventors. None of the authors receive any support or remuneration related to this platform. No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Medical Oncology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium

    Sofie Wilgenhof & Bart Neyns

  2. Laboratory of Molecular and Cellular Therapy and Dendritic Cell-Bank, Vrije Universiteit Brussel, Brussels, Belgium

    Sofie Wilgenhof, Jurgen Corthals, An M. T. Van Nuffel, Daphné Benteyn, Carlo Heirman, Aude Bonehill & Kris Thielemans

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  1. Sofie Wilgenhof
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Correspondence to Sofie Wilgenhof or Bart Neyns.

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Wilgenhof, S., Corthals, J., Van Nuffel, A.M.T. et al. Long-term clinical outcome of melanoma patients treated with messenger RNA-electroporated dendritic cell therapy following complete resection of metastases. Cancer Immunol Immunother 64, 381–388 (2015). https://doi.org/10.1007/s00262-014-1642-8

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