The T-win® technology: immune-modulating vaccines
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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.
KeywordsT-win technology Immune-modulating vaccines Anti-Tregs IDO PD-L1 Arginase
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.
Compliance with ethical standards
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.
- 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
- 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):3520–3530CrossRefGoogle Scholar
- 22.Mullard A (2018) IDO takes a blow. Nat Rev Drug Discov 17(5):307Google 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):221–232CrossRefGoogle 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):197–203CrossRefGoogle 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):544–548CrossRefGoogle 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):2273–2280CrossRefGoogle 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):464–472CrossRefGoogle 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):942–949CrossRefGoogle 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):2000–2009CrossRefGoogle 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. CrossRefGoogle Scholar