CIBSS - Centre for integrative Biological Signalling StudiesCIBSS

Associate Investigators

Prof. Dr. Robert Zeiser

Prof. Dr. Robert Zeiser

Contact

Prof. Dr. Robert Zeiser
Department of Internal Medicine I
University Medical Center, Faculty of Medicine

T +49 761 270 34580
robert.zeiser(at)uniklinik-freiburg.de

Further Information

The work of my group is focused on oncogenic signaling mechanisms that regulate immune responses against tumor cells, with a particular focus on leukemia and melanoma. Immunotherapeutic measures that we apply include mainly  allogeneic hematopoietic cell transplantation (allo-HCT) and immune checkpoint blocker (ICB)-based therapy.

We aim to improve the anti-tumor immune response in these settings by combination therapies that are often based on a link between oncogenic signaling and immune escape, e.g. kinase inhibition and T cell transfer for FLT3-ITD AML, ICB for JAK2 mutant MPN, ICB and miR146a antagomir for melanoma, IL-1β / NLRP3 inhibition for KRAS-G12D driven leukemia and allo-HCT and lactic acid neutralization for AML. These immunotherapeutic interventions cause immune mediated side effects which include acute graft-versus-host disease (GVHD) after allo-HCT and immune related adverse events (irAEs) after ICB therapy. We could show a role for ATP and uric acid acting on the Nlrp3 inflammasome in GVHD. For irAEs we found that extracorporal photopheresis was effective. We found in mice that JAK1/2 inhibition reduces GVHD which led to a positive phase-III trial and the FDA approval of the JAK1/2 inhibitor ruxolitinib for acute GVHD. 

 

Keywords

Tumor immunology, oncogenic signaling, allogeneic hematopoietic cell transplantation (allo-HCT), Graft-versus-host disease (GVHD), Anti-leukemia immune responses, immune checkpoint blockade therapy (ICB), immune related adverse events (irAEs).

10 selected publications:

  • Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease.
    Zeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, Musso M, Giebel S, Uzay A, Langmuir P, Hollaender N, Gowda M, Stefanelli T, Lee SJ, Teshima T, Locatelli F; REACH3 Investigators (2021).
    N Engl J Med. 385(3):228-238.
  • Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation.
    Hamarsheh S, Osswald L, Saller BS, Unger S, De Feo D, Vinnakota JM, Konantz M, Uhl FM, Becker H, Lübbert M, Shoumariyeh K, Schürch C, Andrieux G, Venhoff N, Schmitt-Graeff A, Duquesne S, Pfeifer D, Cooper MA, Lengerke C, Boerries M, Duyster J, Niemeyer CM, Erlacher M, Blazar BR, Becher B, Groß O, Brummer T, Zeiser R (2020).
    Nat Commun. 11(1):1659.
  • Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans.
    Uhl FM, Chen S, O'Sullivan D, Edwards-Hicks J, Richter G, Haring E, Andrieux G, Halbach S, Apostolova P, Büscher J, Duquesne S, Melchinger W, Sauer B, Shoumariyeh K, Schmitt-Graeff A, Kreutz M, Lübbert M, Duyster J, Brummer T, Boerries M, Madl T, Blazar BR, Groß O, Pearce EL, Zeiser R (2020).
    Sci Transl Med. 12(567):eabb8969.
  • Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia.
    Mathew N, Vinnakota JM, Apostolova P, Erny D, Hamarsheh S, Andrieux G, Kim JS, Hanke K, Goldmann T, Chappell-Maor L, El-Khawanky N, Ihorst G, Schmidt D, Duyster J, Finke J, Blank T, Boerries M, Blazar BR, Jung S, Prinz M, Zeiser R (2020).
    J Clin Invest. 130:1315-29
  • Extracorporeal photopheresis for severe immune checkpoint inhibitor-induced autoimmune colitis.
    Apostolova P, Unger S, Meiss F, von Bubnoff D, Aumann K, Becher B, Zeiser R (2019).
    The New England Journal of Medicine 382: 294-6, 2020
  • Immunization against poly-N-acetylglucosamine reduces neutrophil activation and GVHD while sparing microbial diversity.
    Hülsdünker J, Thomas OS, Haring E, Unger S, Gonzalo Núñez N, Tugues S, Gao Z, Duquesne S, Cywes-Bentley C, Oyardi O, Kirschnek S, Schmitt-Graeff A, Pabst O, Koenecke C, Duyster J, Apostolova P, Blaser MJ, Becher B, Pier GB, Häcker G, Zeiser R (2019).
    Proc Natl Acad Sci U S A. 116(41):20700-20706
  • Oncogenic JAK2V617F causes PD-L1 expression mediating immune-escape in myeloproliferative neoplasms.
    Prestipino A, Emhardt A, Aumann K, O´Sullivan D, Gorantla SP, Duquesne S, Melchinger W, Braun L, Vuckovic S, Boerries M, Busch H, Halbach S, Pennisi S, Poggio T, Apostolova P, Veratti P, Hettich M, Niedermann G, Bartholomä M, Shoumariyeh K, Jutzi J, Wehrle J, Dierks C, Becker H, Schmitt-Graeff A, Follo M, Pfeifer D, Rohr J, Fuchs S, Ehl S, Hartl FA, Minguet S, Miething C, Heidel F, Kröger N, Triviai I, Brummer T, Finke J, Illert AL, Ruggiero E, Bonini C, Duyster J, Pahl HL, Lane SW, Hill GR, Blazar BR, Bubnoff N, Pearce EL, Zeiser R (2018). Sci Transl Med. 10 (429)
  • Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD mutant leukemia cells.
    Mathew NR, Baumgartner F, Braun L, David O´Sullivan, Thomas S, Waterhouse M, Müller TA, Hanke K, Taromi S, Apostolova P, Illert AL, Melchinger W, Duquesne S, Schmitt-Graeff A, Osswald L, Yan K-L., Weber A, Tugues S, Spath S, Pfeifer D, Follo M, Claus R, Lübbert M, Rummelt C, Bertz H, Wäsch R, Haag J, Schmidts A, Schultheiss M, Bettinger M, Thimme R, Ullrich E, Tanriver Y, Vuong GL, Arnold R, Hemmati P, Wolf D, Ditschkowski M, Jilg C, Wilhelm K, Leiber C, Gerull S, Halter J, Lengerke C, Pabst T, Schroeder T, Kobbe G, Rösler W, Doostkam S, Meckel S, Stabla K, Metzelder SK, Halbach S, Brummer T, Hu Z, Dengjel J, Hackanson B, Schmid C, Holtick U, Scheid C, Spyridonidis A, Stölzel F, Ordemann F, Müller LP, Sicre-de-Fontbrune F, Ihorst G, Kuball J, Ehlert JE, Feger D, Wagner EV, Cahn JY, Schnell J, Kuchenbauer F, Bunjes D, Chakraverty R, Richardson S, Gill S, Kröger N, Ayuk F, Vago L, Ciceri F, Müller AM, Kondo T, Teshima T, Klaeger S, Kuster B, Kim D, Weisdorf D, van der Velden W, Dörfel D, Bethge W, Hilgendorf I, Hochhaus A, Andrieux G, Börries M, Busch H, Magenau J, Reddy P, Labopin M, H. Antin J, Henden AS, Hill GR, Kennedy GA, Bar M, Sarma A, McLornan D, Mufti G, Oran B, Rezvani K, Sha O, Negrin RS, Nagler A, Prinz M, Burchert A, Neubauer A, Beelen D, Mackensen A, von Bubnoff N, Herr W, Becher B, Socié G, Caligiuri MA, Ruggiero E, Bonini C, Häcker G, Duyster J, Finke J, Pearce E, Blazar BR, Zeiser R (2018).
    Nat Medicine 24: 282-291
  • Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage.
    Schwab L, Goroncy L, Palaniyandi S, Gautam S, Triantafyllopoulou A, Mocsai A, Reichardt W, Karlsson FJ, Radhakrishnan SV, Hanke K, Schmitt-Graeff A, Freudenberg M, von Loewenich FD, Wolf P, Leonhardt F, Baxan N, Pfeifer D, Schmah O, Schönle A, Martin SF, Mertelsmann R, Duyster J, Finke J, Prinz M, Henneke P, Häcker H, Hildebrandt GC, Häcker G, Zeiser R (2014).
    Nat Med. 20(6):648-54.
  • Graft-versus-host disease is enhanced by extracellular ATP activating P2X(7)R.
    Wilhelm K, Ganesan J, Müller T, Dürr C, Grimm M, Beilhack A, Krempl CD, Sorichter S, Gerlach UV, Jüttner E, Zerweck A, Gärtner F, Pellegatti P, Di Virgilio F, Ferrari D, Kambham N, Fisch P, Finke J, *Idzko M, *Zeiser R (2010).
    Nature Medicine 12, 1434-1438
    *contributed equally