TP12 Fulda/Ullrich

Overcoming inefficient tumor immunity by Smac mimetics

Abstract:

The project aims at investigating the therapeutic potential of Smac mimetics to overcome inefficient tumor immunity. We hypothesize that antagonizing IAP proteins by Smac mimetics provides a double-hit strategy to enhance the efficacy of NK cell-based immunotherapy by concomitantly targeting cancer and immune cells. Using in vitro and in vivo models of rhabdomyosarcoma, we will analyze the immunomodulatory functions of Smac mimetics in tumor as well as in NK cells. The results of this project are expected to open new perspectives for developing novel immunomodulating therapies against cancer to circumvent immune escape mechanisms.

Principal investigators:

Prof. Dr. med. Simone Fulda
Institut für Experimentelle Tumorforschung in der Pädiatrie
Goethe-Universität Frankfurt
Komturstraße 3a, 60528 Frankfurt
Phone: +49 (0)69 6786 6557
E-mail: simone.fulda@kgu.de
Web: http://www.kinderkrebsstiftung-frankfurt.de/index.php/forschen/institut-fuer-experimentelle-tumorforschung-in-der-paediatrie/prof-dr-simone-fulda

Prof. Dr. med. Evelyn Ullrich
Zelluläre Immunologie
Klinik für Kinder- und Jugendmedizin
Goethe-Universität Frankfurt
Theodor-Stern-Kai 7, 60590 Frankfurt
Phone: +49 (0)69 6301 83818
E-mail: evelyn.ullrich@kgu.de
Web: https://www.kgu.de/einrichtungen/kliniken/zentrum-der-kinder-und-jugendmedizin/klinik-fuer-kinder-und-jugendmedizin/schwerpunkt-stammzelltransplantation-immunologie-und-intensivmedizin/english-website/experimental-immunology/

Doctoral candidates:

Nawid Albinger

Tobias Bexte (MD)

Julia Campe

Vinzenz Särchen

 

Project-related publications:

Wagner J, Pfannenstiel V, Waldmann A, Bergs JW, Brill B, Huenecke S, Klingebiel T, Rödel F, Buchholz CJ, Wels WS, Bader P, Ullrich E (2017) Two-Phase Expansion Protocol Combining IL-15 and IL-21 Improves NK Cell Proliferation and Cytotoxicity Against Rhabdomyosarcoma. Front Immunol. 8, 676

Rohde K, Kleinesudeik L, Roesler S, Loewe O, Heidler J, Schroeder K, Wittig I, Droese S, Fulda S (2017) A Bak-dependent mitochondrial amplification step contributes to Smac mimetic/glucocorticoid-induced necroptosis. Cell Death Differ. 24, 83-97

Fischer K, Tognarelli S, Rösler S, Boedicker C, Schubert R, Steinle A, Klingebiel T, Bader P, Fulda S, Ullrich E (2017) The Smac mimetic BV6 improves NK cell mediated killing of rhabdomyosarcoma cells by simultaneously targeting tumor and effector cells. Front Immunol. 8, 202

Tchoghandjian A, Jennewein C, Eckhardt I, Momma S, Figarella-Branger D, Fulda S (2014) Smac mimetic promotes glioblastoma cancer stem-like cell differentiation by activating NF-kappaB. Cell Death Differ 21:735-747

Belz K, Schoeneberger H, Wehner S, Weigert A, Bönig H, Klingebiel T, Fichtner I, Fulda S (2014) Smac mimetic and glucocorticoids synergize to induce apoptosis in childhood ALL by promoting ripoptosome assembly. Blood 124:240-250

Eckhardt I, Weigert A, Fulda S (2014) Identification of IRF1 as critical dual regulator of Smac mimetic-induced apoptosis and inflammatory cytokine response. Cell Death Dis, 5:e1562.

Ullrich E, Koch J, Cerwenka A, Steinle A (2013) New prospects on the NKG2D/NKG2DL system for oncology. Oncoimmunology 2:e26097

Meinhardt K, Kroeger I, Abendroth A, Muller S, Mackensen A, Ullrich E (2012) Influence of NK cell magnetic bead isolation methods on phenotype and function of murine NK cells. J Immunol Methods 378:1-10

Loeder S, Fakler M, Schoeneberger H, Cristofanon S, Leibacher J, Vanlangenakker N, Bertrand MJ, Vandenabeele P, Jeremias I, Debatin KM, Fulda S (2012) RIP1 is required for IAP inhibitor-mediated sensitization of childhood acute leukemia cells to chemotherapy-induced apoptosis. Leukemia 26:1020-1029

Terme M, Ullrich E, Delahaye NF, Chaput N, Zitvogel L (2008) Natural killer cell-directed therapies: moving from unexpected results to successful strategies. Nat Immunol 9:486-494