[go: up one dir, main page]
More Web Proxy on the site http://driver.im/ Skip to main content

Advertisement

Springer Nature Link
Log in

Optimized dendritic cell-based immunotherapy for melanoma: the TriMix-formula

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Since decades, the main goal of tumor immunologists has been to increase the capacity of the immune system to mediate tumor regression. In this regard, one of the major focuses of cancer immunotherapy has been the design of vaccines promoting strong tumor-specific cytotoxic T lymphocyte responses in cancer patients. Here, dendritic cells (DCs) play a pivotal role as they are regarded as nature’s adjuvant and as such have become the natural agents for antigen delivery in order to finally elicit strong T cell responses (Villadangos and Schnorrer in Nat Rev Immunol 7:543–555, 2007; Melief in Immunity 29:372–383, 2008; Palucka and Banchereau in Nat Rev Cancer 12:265–277, 2012; Vacchelli et al. in Oncoimmunology 2:e25771, 2013; Galluzzi et al. in Oncoimmunology 1:1111–1134, 2012). Therefore, many investigators are actively pursuing the use of DCs as an efficient way of inducing anticancer immune responses. Nowadays, DCs can be generated at a large scale in closed systems, yielding sufficient numbers of cells for clinical application. In addition, with the identification of tumor-associated antigens, which are either selectively or preferentially expressed by tumors, a whole range of strategies using DCs for immunotherapy have been designed and tested in clinical studies. Despite the evidence that DCs loaded with tumor-associated antigens can elicit immune responses in vivo, clinical responses remained disappointingly low. Therefore, optimization of the cellular product and route of administration was urgently needed. Here, we review the path we have followed in the development of TriMixDC-MEL, a potent DC-based cellular therapy, discussing its development as well as further modifications and applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
£29.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

API:

Active pharmaceutical ingredient

caTLR4:

Constitutive active form of Toll-like receptor 4

CD40L:

CD40 ligand

CTLA-4:

Cytotoxic T-Lymphocyte antigen 4

CTLs:

Cytotoxic T lymphocytes

DCs:

Dendritic cells

DTH:

Delayed-type hypersensitivity

GM-CSF:

Granulocyte/macrophage colony-stimulating factor

GMP:

Good manufacturing practice

HBSS:

Hanks balanced salt solution

HLA:

Human leukocyte antigen

i.d.:

Intradermal

i.n.:

Intranodal

i.v.:

Intravenous

mAbs:

Monoclonal antibodies

MP:

Medicinal product

NGS:

Next-generation sequencing

SKILs:

Skin-infiltrating lymphocytes

TH1:

T helper 1

TLR:

Toll-like receptor

Treg:

Regulatory T cell

TriMixDC-MEL:

TriMixDCs co-electroporated with mRNA encoding a fusion of DC-LAMP and one of four melanoma-associated antigens: gp100, tyrosinase, MAGE-A3 and MAGE-C2

References

  1. Villadangos JA, Schnorrer P (2007) Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol 7:543–555

    CAS  PubMed  Google Scholar 

  2. Melief CJM (2008) Cancer immunotherapy by dendritic cells. Immunity 29:372–383

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Vacchelli E, Vitale I, Eggermont A et al (2013) Trial watch: dendritic cell-based interventions for cancer therapy. Oncoimmunology 2:e25771

    Article  PubMed Central  PubMed  Google Scholar 

  5. Galluzzi L, Senovilla L, Vacchelli E et al (2012) Trial watch: dendritic cell-based interventions for cancer therapy. Oncoimmunology 1:1111–1134

    Article  PubMed Central  PubMed  Google Scholar 

  6. Jonuleit H, Giesecke-Tuettenberg A, Tüting T et al (2001) A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection. Int J Cancer 93:243–251

    CAS  PubMed  Google Scholar 

  7. De Vries IJM, Lesterhuis WJ, Scharenborg NM et al (2003) Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients. Clin Cancer Res 9:5091–5100

    PubMed  Google Scholar 

  8. Steinman RM, Nussenzweig MC (2002) Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci U S A 99:351–358

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Lutz MB, Schuler G (2002) Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol 23:445–449

    Article  CAS  PubMed  Google Scholar 

  10. Cools N, Van Tendeloo VFI, Smits ELJM et al (2008) Immunosuppression induced by immature dendritic cells is mediated by TGF-beta/IL-10 double-positive CD4+ regulatory T cells. J Cell Mol Med 12:690–700

    CAS  PubMed  Google Scholar 

  11. Enk AH (2005) Dendritic cells in tolerance induction. Immunol Lett 99:8–11

    Article  CAS  PubMed  Google Scholar 

  12. Jonuleit H, Kühn U, Müller G et al (1997) Pro-inflammatory cytokines and prostaglandins induce maturation of potent immunostimulatory dendritic cells under fetal calf serum-free conditions. Eur J Immunol 27:3135–3142

    Article  CAS  PubMed  Google Scholar 

  13. Mailliard RB, Wankowicz-Kalinska A, Cai Q et al (2004) Alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. Cancer Res 64:5934–5937

    Article  CAS  PubMed  Google Scholar 

  14. Vonderheide RH, Flaherty KT, Khalil M et al (2007) Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol 25:876–883

    Article  CAS  PubMed  Google Scholar 

  15. Turner JG, Rakhmilevich AL, Burdelya L et al (2001) Anti-CD40 antibody induces antitumor and antimetastatic effects: the role of NK cells. J Immunol 166:89–94

    Article  CAS  PubMed  Google Scholar 

  16. Nair S, McLaughlin C, Weizer A et al (2003) Injection of immature dendritic cells into adjuvant-treated skin obviates the need for ex vivo maturation. J Immunol 171:6275–6282

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  18. Calderhead DM, DeBenedette MA, Ketteringham H et al (2008) Cytokine maturation followed by CD40L mRNA electroporation results in a clinically relevant dendritic cell product capable of inducing a potent proinflammatory CTL response. J Immunother 31:731–741

    Article  CAS  PubMed  Google Scholar 

  19. DeBenedette MA, Calderhead DM, Tcherepanova IY et al (2011) Potency of mature CD40L RNA electroporated dendritic cells correlates with IL-12 secretion by tracking multifunctional CD8(+)/CD28(+) cytotoxic T-cell responses in vitro. J Immunother 34:45–57

    Article  CAS  PubMed  Google Scholar 

  20. Bonehill A, Tuyaerts S, Van Nuffel AMT et al (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 

  21. Kikuchi T, Moore MA, Crystal RG (2000) Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors. Blood 96:91–99

    CAS  PubMed  Google Scholar 

  22. Cisco RM, Abdel-Wahab Z, Dannull J et al (2004) Induction of human dendritic cell maturation using transfection with RNA encoding a dominant positive toll-like receptor 4. J Immunol 172:7162–7168

    Article  CAS  PubMed  Google Scholar 

  23. Borst J, Hendriks J, Xiao Y (2005) CD27 and CD70 in T cell and B cell activation. Curr Opin Immunol 17:275–281

    Article  CAS  PubMed  Google Scholar 

  24. Van Lint S, Van Nuffel AM, Wilgenhof S, et al. (2013) Priming of cytotoxic T lymphocyte responses by dendritic cells: induction of potent anti-tumor immune responses. Cytotoxic T lymphocytes Mech Dev Dis, Horizons i. Nova Science Publishers, p volume 51

  25. Langenkamp A, Messi M, Lanzavecchia A, Sallusto F (2000) Kinetics of dendritic cell activation: impact on priming of TH1, TH2 and nonpolarized T cells. Nat Immunol 1:311–316

    Article  CAS  PubMed  Google Scholar 

  26. Bonehill A, Van Nuffel AMT, 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 

  27. Wilgenhof S, Van Nuffel AMT, 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 

  28. Pen JJ, De Keersmaecker B, Maenhout SK et al (2013) Modulation of regulatory T cell function by monocyte-derived dendritic cells matured through electroporation with mRNA encoding CD40 ligand, constitutively active TLR4, and CD70. J Immunol 191:1976–1983

    Article  CAS  PubMed  Google Scholar 

  29. Fong L, Brockstedt D, Benike C et al (2001) Dendritic cells injected via different routes induce immunity in cancer patients. J Immunol 166:4254–4259

    Article  CAS  PubMed  Google Scholar 

  30. Mullins DW, Sheasley SL, Ream RM et al (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 198:1023–1034

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  32. Wilgenhof S, Van Nuffel AMT, 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 

  33. Van Elsas A, Hurwitz AA, Allison JP (1999) Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied. J Exp Med 190:355–366

    Article  PubMed Central  PubMed  Google Scholar 

  34. Neyns B, Wilgenhof S, Van Nuffel AMT et al (2011) A phase I clinical trial on the combined intravenous (IV) and intradermal (ID) administration of autologous TriMix-DC cellular therapy in patients with pretreated melanoma (TriMixIDIV). ASCO Meet Abstr 29:2519

    Google Scholar 

  35. Van Lint S, Heirman C, Thielemans K, Breckpot K (2013) mRNA: from a chemical blueprint for protein production to an off-the-shelf therapeutic. Hum Vaccin Immunother 9(2):265–274

    Article  PubMed Central  PubMed  Google Scholar 

  36. Van Lint S, Goyvaerts C, Maenhout S et al (2012) Preclinical evaluation of TriMix and antigen mRNA-based antitumor therapy. Cancer Res 72:1661–1671

    Article  PubMed  Google Scholar 

  37. Kuhn AN, Diken M, Kreiter S et al (2011) Determinants of intracellular RNA pharmacokinetics: implications for RNA-based immunotherapeutics. RNA Biol 8:35–43

    Article  CAS  PubMed  Google Scholar 

  38. Probst J, Brechtel S, Scheel B et al (2006) Characterization of the ribonuclease activity on the skin surface. Genet Vaccines Ther 4:4

    Article  PubMed Central  PubMed  Google Scholar 

  39. Diken M, Kreiter S, Selmi A et al (2011) Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation. Gene Ther 18:702–708

    Article  CAS  PubMed  Google Scholar 

  40. Kreiter S, Diken M, Selmi A et al (2011) Tumor vaccination using messenger RNA: prospects of a future therapy. Curr Opin Immunol 23:399–406

    Article  CAS  PubMed  Google Scholar 

  41. Pascolo S (2006) Vaccination with messenger RNA. Methods Mol Med 127:23–40

    CAS  PubMed  Google Scholar 

  42. Pascolo S (2004) Messenger RNA-based vaccines. Expert Opin Biol Ther 4:1285–1294

    Article  CAS  PubMed  Google Scholar 

  43. Bringmann A, Held SAE, Heine A, Brossart P (2010) RNA vaccines in cancer treatment. J Biomed Biotechnol 2010:623687

    Article  PubMed Central  PubMed  Google Scholar 

  44. Kuhn AN, Beißert T, Simon P et al (2012) mRNA as a versatile tool for exogenous protein expression. Curr Gene Ther 12:347–361

    Article  CAS  PubMed  Google Scholar 

  45. Ulmer JB, Mason PW, Geall A, Mandl CW (2012) RNA-based vaccines. Vaccine 30:4414–4418

    Article  CAS  PubMed  Google Scholar 

  46. Kreiter S, Castle JC, Türeci O, Sahin U (2012) Targeting the tumor mutanome for personalized vaccination therapy. Oncoimmunology 1:768–769

    Article  PubMed Central  PubMed  Google Scholar 

  47. Castle JC, Kreiter S, Diekmann J et al (2012) Exploiting the mutanome for tumor vaccination. Cancer Res 72:1081–1091

    Article  CAS  PubMed  Google Scholar 

  48. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  CAS  PubMed  Google Scholar 

  49. Britten CM, Singh-Jasuja H, Flamion B et al (2013) The regulatory landscape for actively personalized cancer immunotherapies. Nat Biotechnol 31:880–882

    Article  CAS  PubMed  Google Scholar 

  50. Le Dieu R, Taussig DC, Ramsay AG et al (2009) Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts. Blood 114:3909–3916

    Article  PubMed Central  PubMed  Google Scholar 

  51. Ramsay AG, Clear AJ, Kelly G et al (2009) Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood 114:4713–4720

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Ramsay AG, Johnson AJ, Lee AM et al (2008) Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest 118:2427–2437

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363:711–723

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Brahmer JR, Tykodi SS, Chow LQM et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Pruitt SK, Boczkowski D, de Rosa N et al (2011) Enhancement of anti-tumor immunity through local modulation of CTLA-4 and GITR by dendritic cells. Eur J Immunol 41:3553–3563

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the patients for their participation in the clinical studies, their families and caregivers, the staff of the Laboratorium of Molecular and Cellular Therapy (LMCT) and the Dendritic Cell Bank for their technical assistance and eTheRNA for providing mRNA. The work described was supported by grants from the Interuniversity Attraction Poles Program—Belgian State (P7/39)—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.

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 conflict of interests were disclosed.

Author information

Authors and Affiliations

  1. Laboratory of Molecular and Cellular Therapy & Dendritic Cell-bank, Vrije Universiteit Brussel, Laarbeeklaan 103E, 1090, Brussels, Belgium

    Sandra Van Lint, Sofie Wilgenhof, Carlo Heirman, Jurgen Corthals, Karine Breckpot, Aude Bonehill & Kris Thielemans

  2. Department of Medical Oncology, University Hospital Brussel (UZ Brussel), Brussels, Belgium

    Sofie Wilgenhof, Bart Neyns & Kris Thielemans

Authors
  1. Sandra Van Lint
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sofie Wilgenhof
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carlo Heirman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jurgen Corthals
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karine Breckpot
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aude Bonehill
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bart Neyns
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kris Thielemans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kris Thielemans.

Additional information

Sandra Van Lint and Sofie Wilgenhof contributed equally to this work.

This paper is a Focussed Research Review based on a presentation given at the 19th Danish Cancer Society Symposium in Copenhagen, Denmark, 23rd–25th September 2013, on the topic “Immunotherapy of Cancer—Present Status and Future Promise”. It is part of a CII series of Focussed Research Reviews and meeting report.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Van Lint, S., Wilgenhof, S., Heirman, C. et al. Optimized dendritic cell-based immunotherapy for melanoma: the TriMix-formula. Cancer Immunol Immunother 63, 959–967 (2014). https://doi.org/10.1007/s00262-014-1558-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-014-1558-3

Keywords

Search

Navigation