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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

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Abstract

Dendritic cells (DCs) electroporated with mRNA encoding CD70, CD40L and a constitutively active toll-like receptor 4 (TriMix-DC) have an increased T-cell stimulatory capacity. In a prospective phase IB clinical trial, we treated melanoma patients with intradermal and intravenous injections of autologous TriMix-DC co-electroporated with mRNA encoding full-length MAGE-A3, MAGE-C2, tyrosinase and gp100. We report here the immunological and clinical results obtained in one patient with a particularly favorable outcome. This patient had stage IV-M1c melanoma with documented progression during dacarbazine chemotherapy and received 5 TriMix-DC injections. Following DC therapy, a broad CD8+ T-cell response against multiple epitopes derived from all four treatment antigens was found in the blood and among T cells derived from DTH biopsy. In addition, CD4+ T cells recognizing different MAGE-A3-derived epitopes were detected in DTH-derived cells. A spontaneous anti-MAGE-C2 CD8+ T-cell response was present prior to TriMix-DC therapy and increased during treatment. The tumor response was assessed with 18-fluorodeoxyglucose-positron emission/computed tomography. We documented a partial tumor response according to RECIST criteria with a marked reduction in 18F-FDG-uptake by lung, lymph node and bone metastases. The patient remains free from progression after 12 months of follow-up. This case report indicates that administration of autologous TriMix-DC by the combined intradermal and intravenous route can mediate a durable objective tumor response accompanied by a broad T-cell response in a chemorefractory stage IV-M1c melanoma patient.

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References

  1. Lens MB, Dawes M (2004) Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 150(2):179–185

    Article  PubMed  CAS  Google Scholar 

  2. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, Sondak VK (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27(36):6199–6206

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  4. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723

    Article  PubMed  CAS  Google Scholar 

  5. Robert C, Thomas L, Bondarenko I, O’Day S, DJ M, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller WH, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364(26):2517–2526

    Article  PubMed  CAS  Google Scholar 

  6. Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P (2011) gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 364(22):2119–2127

    Article  PubMed  CAS  Google Scholar 

  7. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392(6673):245–252

    Article  PubMed  CAS  Google Scholar 

  8. Palucka K, Ueno H, Fay J, Banchereau J (2011) Dendritic cells and immunity against cancer. J Intern Med 269(1):64–73

    Article  PubMed  CAS  Google Scholar 

  9. Tuyaerts S, Aerts JL, Corthals J, Neyns B, Heirman C, Breckpot K, Thielemans K, Bonehill A (2007) Current approaches in dendritic cell generation and future implications for cancer immunotherapy. Cancer Immunol Immunother 56(10):1513–1537

    Article  PubMed  CAS  Google Scholar 

  10. Lesterhuis WJ, Aarntzen EH, De Vries IJ, Schuurhuis DH, Figdor CG, Adema GJ, Punt CJ (2008) Dendritic cell vaccines in melanoma: from promise to proof? Crit Rev Oncol Hematol 66(2):118–134

    Article  PubMed  CAS  Google Scholar 

  11. Van Nuffel AM, 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 

  12. Mullins DW, Sheasley SL, Ream RM, Bullock TN, Fu YX, Engelhard VH (2003) Route of immunization with peptide-pulsed dendritic cells controls the distribution of memory and effector T cells in lymphoid tissues and determines the pattern of regional tumor control. J Exp Med 198(7):1023–1034

    Article  PubMed  CAS  Google Scholar 

  13. Fong L, Brockstedt D, Benike C, Wu L, Engleman EG (2001) Dendritic cells injected via different routes induce immunity in cancer patients. J Immunol 166(6):4254–4259

    PubMed  CAS  Google Scholar 

  14. Sheasley-O’Neill SL, Brinkman CC, Ferguson AR, Dispenza MC, Engelhard VH (2007) Dendritic cell immunization route determines integrin expression and lymphoid and nonlymphoid tissue distribution of CD8 T cells. J Immunol 178(3):1512–1522

    PubMed  Google Scholar 

  15. Ferguson AR, Nichols LA, Zarling AL, Thompson ED, Brinkman CC, Hargadon KM, Bullock TN, Engelhard VH (2008) Strategies and challenges in eliciting immunity to melanoma. Immunol Rev 222:28–42

    Article  PubMed  CAS  Google Scholar 

  16. Bonehill A, Van Nuffel AM, Corthals J, Tuyaerts S, Heirman C, Francois V, Colau D, van der Bruggen P, Neyns B, Thielemans K (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(10):3366–3375

    Article  PubMed  CAS  Google Scholar 

  17. 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(11):6649–6657

    PubMed  CAS  Google Scholar 

  18. 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(6):1170–1180

    Article  PubMed  CAS  Google Scholar 

  19. Wilgenhof S, Van Nuffel AM, Corthals J, Heirman C, Tuyaerts S, Benteyn D, De Coninck A, Van Riet I, Verfaillie G, Vandeloo J, Bonehill A, Thielemans K, Neyns B (2011) Therapeutic vaccination with an autologous mRNA electroporated dendritic cell vaccine in patients with advanced melanoma. J Immunother 34(5):448–456

    Article  PubMed  CAS  Google Scholar 

  20. Adema GJ, de Vries IJ, Punt CJ, Figdor CG (2005) Migration of dendritic cell based cancer vaccines: in vivo veritas? Curr Opin Immunol 17(2):170–174

    Google Scholar 

  21. Butcher EC, Williams M, Youngman K, Rott L, Briskin M (1999) Lymphocyte trafficking and regional immunity. Adv Immunol 72:209–253

    Article  PubMed  CAS  Google Scholar 

  22. Ferguson AR, Engelhard VH (2010) CD8 T cells activated in distinct lymphoid organs differentially express adhesion proteins and coexpress multiple chemokine receptors. J Immunol 184(8):4079–4086

    Article  PubMed  CAS  Google Scholar 

  23. Morikawa Y, Tohya K, Ishida H, Matsuura N, Kakudo K (1995) Different migration patterns of antigen-presenting cells correlate with Th1/Th2-type responses in mice. Immunology 85(4):575–581

    PubMed  CAS  Google Scholar 

  24. Morse MA, Coleman RE, Akabani G, Niehaus N, Coleman D, Lyerly HK (1999) Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res 59(1):56–58

    PubMed  CAS  Google Scholar 

  25. Grover A, Kim GJ, Lizee G, Tschoi M, Wang G, Wunderlich JR, Rosenberg SA, Hwang ST, Hwu P (2006) Intralymphatic dendritic cell vaccination induces tumor antigen-specific, skin-homing T lymphocytes. Clin Cancer Res 12(19):5801–5808

    Article  PubMed  CAS  Google Scholar 

  26. Kantoff PW, Higano CS, Shore ND, Berger ER, 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(5):411–422

    Article  PubMed  CAS  Google Scholar 

  27. Engell-Noerregaard L, Hansen TH, Andersen MH, Thor Straten P, 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):1–14

    Article  PubMed  CAS  Google Scholar 

  28. Ayyoub M, Rimoldi D, Guillaume P, Romero P, Cerottini JC, Valmori D, Speiser D (2003) Tumor-reactive, SSX-2-specific CD8+ T cells are selectively expanded during immune responses to antigen-expressing tumors in melanoma patients. Cancer Res 63(17):5601–5606

    PubMed  CAS  Google Scholar 

  29. Gnjatic S, Atanackovic D, Jager E, Matsuo M, Selvakumar A, Altorki NK, Maki RG, Dupont B, Ritter G, Chen YT, Knuth A, Old LJ (2003) Survey of naturally occurring CD4+ T cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses. Proc Natl Acad Sci USA 100(15):8862–8867

    Article  PubMed  CAS  Google Scholar 

  30. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, Jungbluth AA, Frosina D, Gnjatic S, Ambrosone C, Kepner J, Odunsi T, Ritter G, Lele S, Chen YT, Ohtani H, Old LJ, Odunsi K (2005) Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA 102(51):18538–18543

    Article  PubMed  CAS  Google Scholar 

  31. Hanagiri T, van Baren N, Neyns B, Boon T, Coulie PG (2006) Analysis of a rare melanoma patient with a spontaneous CTL response to a MAGE-A3 peptide presented by HLA-A1. Cancer Immunol Immunother 55(2):178–184

    Article  PubMed  Google Scholar 

  32. Speiser DE, Baumgaertner P, Barbey C, Rubio-Godoy V, Moulin A, Corthesy P, Devevre E, Dietrich PY, Rimoldi D, Lienard D, Cerottini JC, Romero P, Rufer N (2006) A novel approach to characterize clonality and differentiation of human melanoma-specific T cell responses: spontaneous priming and efficient boosting by vaccination. J Immunol 177(2):1338–1348

    PubMed  CAS  Google Scholar 

  33. van der Bruggen P, Stroobant V, Vigneron N, Van den Eynde B. http://www.cancerimmunity.org/peptidedatabase/Tcellepitopes.htm. Accessed 28 June 2011

  34. De Plaen E, Arden K, Traversari C, Gaforio JJ, Szikora JP, De Smet C, Brasseur F, van der Bruggen P, Lethe B, Lurquin C et al (1994) Structure, chromosomal localization, and expression of 12 genes of the MAGE family. Immunogenetics 40(5):360–369

    Article  PubMed  CAS  Google Scholar 

  35. Corbiere V, Chapiro J, Stroobant V, Ma W, Lurquin C, Lethe B, van Baren N, Van den Eynde BJ, Boon T, Coulie PG (2011) Antigen spreading contributes to MAGE vaccination-induced regression of melanoma metastases. Cancer Res 71(4):1253–1262

    Article  PubMed  CAS  Google Scholar 

  36. Hardwick N, Chain B (2011) Epitope spreading contributes to effective immunotherapy in metastatic melanoma patients. Immunotherapy 3(6):731–733

    Article  PubMed  CAS  Google Scholar 

  37. de Vries IJ, Bernsen MR, Lesterhuis WJ, Scharenborg NM, Strijk SP, Gerritsen MJ, Ruiter DJ, Figdor CG, Punt CJ, Adema GJ (2005) Immunomonitoring tumor-specific T cells in delayed-type hypersensitivity skin biopsies after dendritic cell vaccination correlates with clinical outcome. J Clin Oncol 23(24):5779–5787

    Article  PubMed  Google Scholar 

  38. Edele F, Molenaar R, Gutle D, Dudda JC, Jakob T, Homey B, Mebius R, Hornef M, Martin SF (2008) Cutting edge: instructive role of peripheral tissue cells in the imprinting of T cell homing receptor patterns. J Immunol 181(6):3745–3749

    PubMed  CAS  Google Scholar 

  39. Chen Q, Jackson H, Shackleton M, Parente P, Hopkins W, Sturrock S, MacGregor D, Maraskovsky E, Tai TY, Dimopoulos N, Masterman KA, Luke T, Davis ID, Chen W, Cebon J (2005) Characterization of antigen-specific CD8+ T lymphocyte responses in skin and peripheral blood following intradermal peptide vaccination. Cancer Immun 5:5

    PubMed  Google Scholar 

  40. Bioley G, Jandus C, Tuyaerts S, Rimoldi D, Kwok WW, Speiser DE, Tiercy JM, Thielemans K, Cerottini JC, Romero P (2006) Melan-A/MART-1-specific CD4 T cells in melanoma patients: identification of new epitopes and ex vivo visualization of specific T cells by MHC class II tetramers. J Immunol 177(10):6769–6779

    PubMed  CAS  Google Scholar 

  41. Kyte JA, Trachsel S, Risberg B, thor Straten P, Lislerud K, Gaudernack G (2009) Unconventional cytokine profiles and development of T cell memory in long-term survivors after cancer vaccination. Cancer Immunol Immunother 58(10):1609–1626

    Article  PubMed  CAS  Google Scholar 

  42. Suso EM, Dueland S, Rasmussen AM, Vetrhus T, Aamdal S, Kvalheim G, Gaudernack G (2011) hTERT mRNA dendritic cell vaccination: complete response in a pancreatic cancer patient associated with response against several hTERT epitopes. Cancer Immunol Immunother 60(6):809–818

    Article  PubMed  CAS  Google Scholar 

  43. Annunziato F, Romagnani S (2009) Heterogeneity of human effector CD4+ T cells. Arthritis Res Ther 11(6):257

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank Katrien Van den Bossche and Cindy Aerts for data management; Elsy Vaeremans, Xavier Debaere, Gwenny De Metter, Chiraz Mamhmoud and Carine Wartel for their technical assistance and the department of radiotherapy of the UZ Brussels for the irradiation of the EBV-B cells. The authors also thank Dr. P. Coulie (de Duve Institute, Université catholique de Louvain, Brussels, Belgium) and Dr. P. van der Bruggen (Ludwig Institute for Cancer Research, Brussels Branch) for careful and critical reading of the manuscript. This work was supported by grants from the Interuniversity Attraction Poles Program—Belgian State—Belgian Science Policy, the National Cancer Plan of the Federal Ministry of Health, the Stichting tegen Kanker, the Vlaamse Liga tegen Kanker, an Integrated Project and a Network of Excellence sponsored by the EU FP-6, an IWT-TBM program, the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO-Vlaanderen) and the Willy Gepts Wetenschappelijk Fonds of the UZ Brussel. S. W. is a PhD fellow and A. B. is a postdoctoral fellow of the FWO-Vlaanderen.

Conflict of interest

TriMix-DCs are the topic of a current patent application (WO2009/034172). AB and KT are mentioned as inventors of this application. None of the authors involved in this study receives any form of support or remuneration related to this platform.

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Authors and Affiliations

  1. Laboratory of Molecular and Cellular Therapy, Department of Immunology-Physiology, Vrije Universiteit Brussel, Laarbeeklaan 103/E235, 1090, Brussels, Belgium

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

  2. The Dendritic Cell Bank, Vrije Universiteit Brussel, Brussels, Belgium

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

  3. The Department of Medical Oncology, Universitair Ziekenhuis Brussel, Brussels, Belgium

    Sofie Wilgenhof, Bart Neyns & Kris Thielemans

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  1. An M. T. Van Nuffel
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  2. Daphné Benteyn
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  3. Sofie Wilgenhof
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  4. Jurgen Corthals
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  8. Aude Bonehill
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Correspondence to Aude Bonehill.

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An M. T. Van Nuffel, Daphné Benteyn and Sofie Wilgenhof contributed equally to this work.

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Van Nuffel, A.M.T., Benteyn, D., Wilgenhof, S. et al. 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 (2012). https://doi.org/10.1007/s00262-011-1176-2

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