Molecular T cell immunotherapy and inhibition of tumor immune escape mechanisms
Abstract:
Genetic engineering of T cells with T-cell receptors (TCR) targeting tumor antigens represents a powerful treatment approach for cancer immunotherapy. However, its therapeutic efficacy is often hampered by a variety of endogenous immunosuppressive mechanisms. Myeloid-derived suppressor cells (MDSC) have emerged as one of the key effector populations of tumor immune escape, which may impair adoptive TCR therapy. This project aims to develop a combination strategy to improve TCR-based immunotherapy by analyzing and specific targeting of MDSC-mediated tumor immune escape mechanisms through (i) pharmacological inhibitors, (ii) strategies to prevent expansion of MDSC and (iii) targeted modulation of arginine metabolism of involved immune and tumor cells.
Principal investigators:
Prof. Dr. med. Markus Munder
III. Medizinische Klinik und Poliklinik (Hämatologie, Internistische Onkologie und Pneumologie)
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Langenbeckstraße 1, 55131 Mainz
Phone: +49 (0)6131 17-5948
E-mail: markus.munder@unimedizin-mainz.de
Web: http://www.unimedizin-mainz.de/3-med/arbeitsgruppen/ag-munder/ag-munder/startseite-home.html
Univ.-Prof. Dr. med. Matthias Theobald
III. Medizinische Klinik und Poliklinik (Hämatologie, Internistische Onkologie und Pneumologie)
Universitätsmedizin der Johannes Gutenberg-Universität Mainz
Langenbeckstraße 1, 55131 Mainz
Phone: +49 (0)6131 17-7281
E-mail: direktor-3med@unimedizin-mainz.de
Web: http://www.unimedizin-mainz.de/3-med/arbeitsgruppen/ag-echchannaoui-hauptrock-theobald/startseite-home.html
Doctoral candidates:
Yagmur Bülbül
Alexander Lang
Project-related publications::
Knies D, Klobuch S, Xue SA, Birtel M, Echchannaoui H, Yildiz O, Omokoko T, Guillaume P, Romero P, Stauss H, Sahin U, Herr W, Theobald M, Thomas S, Voss RH (2016) An optimized single chain TCR scaffold relying on the assembly with the native CD3-complex prevents residual mispairing with endogenous TCRs in human T-cells. Oncotarget 16:21199-21221
Werner A, Amann E, Schnitzius V, Habermeier A, Luckner-Minden C, Leuchtner N, Rupp J, Closs EI, Munder M (2016) Induced arginine transport via cationic amino acid transporter-1 is necessary for human T-cell proliferation. Eur J Immunol. 46:92-103
Munder M, Engelhardt M, Knies D, Medenhoff S, Wabnitz G, Luckner-Minden C, Feldmeyer N, Voss RH, Kropf P, Muller I, Conradi R, Samstag Y, Theobald M, Ho AD, Goldschmidt G, Hundemer M (2013) Cytotoxicity of tumor antigen specific human T cells is unimpaired by arginine depletion. PLoS One 8: e63521
Voss RH, Thomas S, Pfirschke C, Hauptrock B, Klobuch S, Kuball J, Grabowski M, Engel R, Guillaume P, Romero P, Huber C, Beckhove P, Theobald M (2010) Coexpression of the T-cell receptor constant alpha domain triggers tumor reactivity of single-chain TCR-transduced human T cells. Blood 115:5154-5163
Oberlies J, Watzl C, Giese T, Luckner C, Kropf P, Muller I, Ho AD, Munder M (2009) Regulation of NK cell function by human granulocyte arginase. J Immunol 182:5259-5267
Kuball J, Hauptrock B, Malina V, Antunes E, Voss RH, Wolfl M, Strong R, Theobald M, Greenberg PD (2009) Increasing functional avidity of TCR-redirected T cells by removing defined N-glycosylation sites in the TCR constant domain. J Exp Med 206:463-475
Munder M, Schneider H, Luckner C, Giese T, Langhans CD, Fuentes JM, Kropf P, Mueller I, Kolb A, Modolell M, Ho AD (2006) Suppression of T-cell functions by human granulocyte arginase. Blood 108:1627-1634
Munder M, Mollinedo F, Calafat J, Canchado J, Gil-Lamaignere C, Fuentes JM, Luckner C, Doschko G, Soler G, Eichmann K, Muller FM, Ho AD, Goerner M, Modolell M (2005) Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 105:2549-2556
Kuball J, Schmitz FW, Voss RH, Ferreira EA, Engel R, Guillaume P, Strand S, Romero P, Huber C, Sherman LA, Theobald M (2005). Cooperation of human tumor-reactive CD4+ and CD8+ T cells after redirection of their specificity by a high-affinity p53A2.1-specific TCR. Immunity 22:117-129
Stanislawski T, Voss RH, Lotz C, Sadovnikova E, Willemsen RA, Kuball J, Ruppert T, Bolhuis RL, Melief CJ, Huber C, Stauss HJ, Theobald M (2001). Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat. Immunol. 2:962-970