Skip to main content

Advertisement

SpringerLink
Log in

The T-win® technology: immune-modulating vaccines

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

The T-win® technology is an innovative investigational approach designed to activate the body’s endogenous anti-regulatory T cells (anti-Tregs) to target regulatory as well as malignant cells. Anti-Tregs are naturally occurring T cells that can directly react against regulatory immune cells because they recognize proteins that these targets express, including indoleamine 2,3-dioxygenase (IDO), tryptophan 2,6-dioxygenase, arginase, and programmed death ligand 1 (PD-L1). The T-win® technology is characterized by therapeutic vaccination with long peptide epitopes derived from these antigens and therefore offers a novel way to target genetically stable cells with regular human leukocyte antigen expression in the tumor microenvironment. The T-win® technology thus also represents a novel way to attract pro-inflammatory cells to the tumor microenvironment where they can directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens. The modification of an immune regulatory environment into a pro-inflammatory milieu potentiates effective anti-tumor T cell responses. Many regulatory immune cells may be reverted into effector cells given the right stimulus. Because T-win® technology is based on the immune-modulatory function of the vaccines, the vaccines activate both CD4 and CD8 anti-Tregs. Of importance, in clinical trials, vaccinations against IDO or PD-L1 to potentiate anti-Tregs have so far proved to be safe, with minimal toxicity.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Scheler M, Wenzel J, Tuting T, Takikawa O, Bieber T, von Bubnoff D (2007) Indoleamine 2,3-dioxygenase (IDO): the antagonist of type I interferon-driven skin inflammation? Am J Pathol 171(6):1936–1943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Popov A, Schultze JL (2008) IDO-expressing regulatory dendritic cells in cancer and chronic infection. J Mol Med 86(2):145–160

    Article  CAS  PubMed  Google Scholar 

  3. Gianchecchi E, Delfino DV, Fierabracci A (2013) Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity. Autoimmun Rev 12(11):1091–1100

    Article  CAS  PubMed  Google Scholar 

  4. Andersen MH (2017) Anti-regulatory T cells. Semin Immunopathol 39(3):317–326

    Article  CAS  PubMed  Google Scholar 

  5. Andersen MH (2015) Immune regulation by self-recognition: novel possibilities for anticancer immunotherapy. J Natl Cancer Inst 107(9):154

    Article  CAS  Google Scholar 

  6. Yu W, Jiang N, Ebert PJ, Kidd BA, Muller S, Lund PJ et al (2015) Clonal deletion prunes but does not eliminate self-specific alphabeta CD8(+) T lymphocytes. Immunity 42(5):929–941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sorensen RB, Hadrup SR, Svane IM, Hjortso MC, thor Straten P, Andersen MH (2011) Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators. Blood 117(7):2200–2210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sorensen RB, Berge-Hansen L, Junker N, Hansen CA, Hadrup SR, Schumacher TN et al (2009) The immune system strikes back: cellular immune responses against indoleamine 2,3-dioxygenase. PLoS One 4(9):e6910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Munir S, Andersen GH, Met O, Donia M, Frosig TM, Larsen SK et al (2013) HLA-restricted cytotoxic T cells that are specific for the immune checkpoint ligand PD-L1 occur with high frequency in cancer patients. Cancer Res 73(6):1674–1776

    Article  CAS  Google Scholar 

  10. Munir S, Andersen GH, Woetmann A, Odum N, Becker JC, Andersen MH (2013) Cutaneous T cell lymphoma cells are targets for immune checkpoint ligand PD-L1-specific, cytotoxic T cells. Leukemia 27(11):2251–2253

    Article  CAS  PubMed  Google Scholar 

  11. Larsen SK, Munir S, Woetmann A, Froesig TM, Odum N, Svane IM et al (2013) Functional characterization of Foxp3-specific spontaneous immune responses. Leukemia 27(12):2332–2340

    Article  CAS  PubMed  Google Scholar 

  12. Martinenaite E, Ahmad SM, Hansen M, Met O, Westergaard MW, Larsen SK et al (2016) CCL22-specific T cells: modulating the immunosuppressive tumor microenvironment. Oncoimmunology 5(11):e1238541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Martinenaite E, Mortensen RE, Hansen M, Holmstrom MO, Ahmad SM, Met O et al (2017) Frequent spontaneous adaptive immune responses towards arginase. Oncoimmunology 7:e1404215. https://doi.org/10.1080/2162402X.2017.1404215

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hjortso MC, Larsen SK, Kongsted P, Met O, Frosig TM, Andersen GH et al (2015) Tryptophan 2,3-dioxygenase (TDO)-reactive T cells differ in their functional characteristics in health and cancer. Oncoimmunology 4(1):e968480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ahmad SM, Martinenaite E, Holmstrom MO, Jorgensen M, Met O, Nastasi C et al (2017) The inhibitory checkpoint, PD-L2, is a target for effector T cells: novel possibilities for immune therapy. Oncoimmunolgy. https://doi.org/10.1080/2162402X.2017.1390641

  16. Andersen MH (2018) The balance players of the adaptive immune system. Cancer Res 78(6):1379–1382

    Article  CAS  PubMed  Google Scholar 

  17. Gulley JL, Madan RA, Pachynski R, Mulders P, Sheikh NA, Trager J et al (2017) Role of antigen spread and distinctive characteristics of immunotherapy in cancer treatment. J Natl Cancer Inst 109(4):2982600

    Article  CAS  Google Scholar 

  18. Prendergast GC, Metz R, Muller AJ (2009) IDO recruits Tregs in melanoma. Cell Cycle 8(12):1818–1819

    Article  CAS  PubMed  Google Scholar 

  19. Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, Leffet L, Hansbury MJ, Thomas B, Rupar M, Waeltz P, Bowman KJ, Polam P, Sparks RB, Yue EW, Li Y, Wynn R, Fridman JS, Burn TC, Combs AP, Newton RC, Scherle PA (2010) Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood 115(17):3520–3530

    Article  CAS  PubMed  Google Scholar 

  20. Smith C, Chang MY, Parker KH, Beury DW, DuHadaway JB, Flick HE et al (2012) IDO is a nodal pathogenic driver of lung cancer and metastasis development. Cancer Discov 2(8):722–735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brochez L, Chevolet I, Kruse V (2017) The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur J Cancer 76:167–182. https://doi.org/10.1016/j.ejca.2017.01.011

    Article  CAS  PubMed  Google Scholar 

  22. Mullard A (2018) IDO takes a blow. Nat Rev Drug Discov 17(5):307

    PubMed  Google Scholar 

  23. Iversen TZ, Engell-Noerregaard L, Ellebaek E, Andersen R, Larsen SK, Bjoern J et al (2014) Long-lasting disease stabilization in the absence of toxicity in metastatic lung cancer patients vaccinated with an epitope derived from Indoleamine 2,3 dioxygenase. Clin Cancer Res 20(1):221–232

    Article  CAS  PubMed  Google Scholar 

  24. Nagata Y, Hanagiri T, Mizukami M, Kuroda K, Shigematsu Y, Baba T, Ichiki Y, Yasuda M, So T, Takenoyama M, Sugio K, Nagashima A, Yasumoto K (2009) Clinical significance of HLA class I alleles on postoperative prognosis of lung cancer patients in Japan. Lung Cancer 65(1):91–97

    Article  PubMed  Google Scholar 

  25. Bjoern J, Iversen TZ, Nitschke NJ, Andersen MH, Svane IM (2016) Safety, immune and clinical responses in metastatic melanoma patients vaccinated with a long peptide derived from indoleamine 2,3-dioxygenase in combination with ipilimumab. Cytotherapy 18(8):1043–1055

    Article  CAS  PubMed  Google Scholar 

  26. Pilotte L, Larrieu P, Stroobant V, Colau D, Dolusic E, Frederick R, de Plaen E, Uyttenhove C, Wouters J, Masereel B, van den Eynde BJ (2012) Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase. Proc Natl Acad Sci U S A 109(7):2497–2502

    Article  PubMed  PubMed Central  Google Scholar 

  27. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M, Guillemin GJ, Miller CL, Lutz C, Radlwimmer B, Lehmann I, von Deimling A, Wick W, Platten M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478(7368):197–203

    Article  CAS  PubMed  Google Scholar 

  28. Yu CP, Song YL, Zhu ZM, Huang B, Xiao YQ, Luo DY (2017) Targeting TDO in cancer immunotherapy. Med Oncol 34(5):73–0933

    Article  PubMed  Google Scholar 

  29. Hsu YL, Hung JY, Chiang SY, Jian SF, Wu CY, Lin YS, Tsai YM, Chou SH, Tsai MJ, Kuo PL (2016) Lung cancer-derived galectin-1 contributes to cancer associated fibroblast-mediated cancer progression and immune suppression through TDO2/kynurenine axis. Oncotarget 7(19):27584–27598

    Article  PubMed  PubMed Central  Google Scholar 

  30. Munir S, Larsen SK, Iversen TZ, Donia M, Klausen TW, Svane IM, Straten P, Andersen MH (2012) Natural CD4(+) T-cell responses against Indoleamine 2,3-dioxygenase. PLoS One 7(4):e34568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Chen Z, O'Shea JJ (2008) Th17 cells: a new fate for differentiating helper T cells. Immunol Res 41(2):87–102

    Article  CAS  PubMed  Google Scholar 

  32. Zou W, Restifo NPT (2010) (H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 10(4):248–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sakaguchi S (2006) Regulatory T cells. Springer Semin Immunopathol 28(1):1–2

    Article  PubMed  Google Scholar 

  34. Sundrud MS, Trivigno C (2013) Identity crisis of Th17 cells: many forms, many functions, many questions. Semin Immunol 25(4):263–272

    Article  CAS  PubMed  Google Scholar 

  35. Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, Kadel III EE, Koeppen H, Astarita JL, Cubas R, Jhunjhunwala S, Banchereau R, Yang Y, Guan Y, Chalouni C, Ziai J, Şenbabaoğlu Y, Santoro S, Sheinson D, Hung J, Giltnane JM, Pierce AA, Mesh K, Lianoglou S, Riegler J, Carano RAD, Eriksson P, Höglund M, Somarriba L, Halligan DL, van der Heijden MS, Loriot Y, Rosenberg JE, Fong L, Mellman I, Chen DS, Green M, Derleth C, Fine GD, Hegde PS, Bourgon R, Powles T (2018) TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554(7693):544–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14(10):1014–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, Smith AM et al (2009) Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis. PLoS Pathog 5(4):e1000371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kozako T, Yoshimitsu M, Fujiwara H, Masamoto I, Horai S, White Y, Akimoto M, Suzuki S, Matsushita K, Uozumi K, Tei C, Arima N (2009) PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients. Leukemia 23(2):375–382

    Article  CAS  PubMed  Google Scholar 

  39. Atanackovic D, Luetkens T, Kroger N (2013) Coinhibitory molecule PD-1 as a potential target for the immunotherapy of multiple myeloma. Leukemia 28:993–1000. https://doi.org/10.1038/leu.2013.310

    Article  CAS  PubMed  Google Scholar 

  40. Yang H, Bueso-Ramos C, Dinardo C, Estecio MR, Davanlou M, Geng QR et al (2014) Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia 28(6):1280–1288

    Article  CAS  PubMed  Google Scholar 

  41. Krejsgaard T, Odum N, Geisler C, Wasik MA, Woetmann A (2012) Regulatory T cells and immunodeficiency in mycosis fungoides and Sezary syndrome. Leukemia 26(3):424–432

    Article  CAS  PubMed  Google Scholar 

  42. Kollgaard T, Petersen SL, Hadrup SR, Masmas TN, Seremet T, Andersen MH, Madsen HO, Vindeløv L, thor Straten P (2005) Evidence for involvement of clonally expanded CD8+ T cells in anticancer immune responses in CLL patients following nonmyeloablative conditioning and hematopoietic cell transplantation. Leukemia 19(12):2273–2280

    Article  CAS  PubMed  Google Scholar 

  43. Ame-Thomas P, Le PJ, Yssel H, Caron G, Pangault C, Jean R et al (2012) Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells. Leukemia 26(5):1053–1063

    Article  CAS  PubMed  Google Scholar 

  44. van de Donk NW, Kamps S, Mutis T, Lokhorst HM (2012) Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma. Leukemia 26(2):199–213

    Article  CAS  PubMed  Google Scholar 

  45. Tamura H, Ishibashi M, Yamashita T, Tanosaki S, Okuyama N, Kondo A, Hyodo H, Shinya E, Takahashi H, Dong H, Tamada K, Chen L, Dan K, Ogata K (2013) Marrow stromal cells induce B7-H1 expression on myeloma cells, generating aggressive characteristics in multiple myeloma. Leukemia 27(2):464–472

    Article  CAS  PubMed  Google Scholar 

  46. Greaves P, Gribben JG (2013) The role of B7 family molecules in hematologic malignancy. Blood 121(5):734–744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Munir S, Andersen GH, Svane IM, Andersen MH (2013) The immune checkpoint regulator PD-L1 is a specific target for naturally occurring CD4+ T cells. Oncoimmunology 2(4):e23991

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ahmad SM, Larsen SK, Svane IM, Andersen MH (2014) Harnessing PD-L1-specific cytotoxic T cells for anti-leukemia immunotherapy to defeat mechanisms of immune escape mediated by the PD-1 pathway. Leukemia 28(1):236–238

    Article  CAS  PubMed  Google Scholar 

  51. Minami T, Minami T, Shimizu N, Yamamoto Y, De VM, Nozawa M et al (2015) Identification of programmed death ligand 1-derived peptides capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+ patients with renal cell carcinoma. J Immunother 38(7):285–291

    Article  CAS  PubMed  Google Scholar 

  52. Dong H, Strome SE, Matteson EL, Moder KG, Flies DB, Zhu G, Tamura H, Driscoll CLW, Chen L (2003) Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J Clin Invest 111(3):363–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, Evdemon-Hogan M, Conejo-Garcia JR, Zhang L, Burow M, Zhu Y, Wei S, Kryczek I, Daniel B, Gordon A, Myers L, Lackner A, Disis ML, Knutson KL, Chen L, Zou W (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10(9):942–949

    Article  CAS  PubMed  Google Scholar 

  54. Ishida T, Ishii T, Inagaki A, Yano H, Komatsu H, Iida S, Inagaki H, Ueda R (2006) Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege. Cancer Res 66(11):5716–5722

    Article  CAS  PubMed  Google Scholar 

  55. Gobert M, Treilleux I, Bendriss-Vermare N, Bachelot T, Goddard-Leon S, Arfi V, Biota C, Doffin AC, Durand I, Olive D, Perez S, Pasqual N, Faure C, Ray-Coquard I, Puisieux A, Caux C, Blay JY, Menetrier-Caux C (2009) Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 69(5):2000–2009

    Article  CAS  PubMed  Google Scholar 

  56. Cao L, Hu X, Zhang J, Huang G, Zhang Y (2014) The role of the CCL22-CCR4 axis in the metastasis of gastric cancer cells into omental milky spots. J Transl Med 12:267. https://doi.org/10.1186/s12967-014-0267-1.:267-0267.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Ahmad SM, Martinenaite E, Hansen M, Junker N, Borch TH, Met O et al (2016) PD-L1 peptide co-stimulation increases immunogenicity of a dendritic cell-based cancer vaccine. Oncoimmunology 5(8):e1202391

    Article  CAS  Google Scholar 

Download references

Sources of support

This work was supported by Herlev Hospital, the Danish Cancer Society, and the Danish Council for Independent Research. The funders had no role in the study design, data collection and analysis, decision to publish, or manuscript preparation.

Author information

Authors and Affiliations

  1. Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, DK-2730, Herlev, Denmark

    Mads Hald Andersen

  2. Department of Immunology and Microbiology, University of Copenhagen, DK-2200, Copenhagen, Denmark

    Mads Hald Andersen

  3. IO Biotech ApS, DK-2200, Copenhagen, Denmark

    Mads Hald Andersen

Authors
  1. Mads Hald Andersen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mads Hald Andersen.

Ethics declarations

Conflict of interest

MHA is an author of several filed patent applications based on the use of CCL2, CCL22, PD-L1, PD-L2, arginase, TDO, or IDO for vaccination. The rights of the patent applications have been transferred to Copenhagen University Hospital, Herlev, according to the Danish Law of Public Inventions at Public Research Institutions. The capital region has licensed some of these patents to the company IO Biotech ApS. MHA is a shareholder and board member of the IO Biotech ApS, which has the purpose of developing immune-modulating vaccines for cancer treatment.

Additional information

This article is a contribution to the special issue on Anti-cancer Immunotherapy: Breakthroughs and Future Strategies - Guest Editor: Mads Hald Andersen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Andersen, M.H. The T-win® technology: immune-modulating vaccines. Semin Immunopathol 41, 87–95 (2019). https://doi.org/10.1007/s00281-018-0695-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-018-0695-8

Keywords

Search

Navigation