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:

• Targeting MDM2 enhances anti-leukemia immunity after allogeneic transplantation via MHC-II and TRAIL-R1/2 upregulation.
  Ho, J.N.H.G., Schmidt D, Lowinus T, Ryoo J, Dopfer EP, Gonzalo Núñez N, Costa-Pereira S, Toffalori C, Punta M, Fetsch V, Wertheimer T, Rittmann MC, Braun LM, Follo M, Briere C, Vinnakota JM, Langenbach M, Koppers F, Shoumariyeh K, Engel H, Rückert T, Märklin M, Holzmayer S, Illert AL, Magon F, Andrieux G, Duquesne S, Pfeifer D, Staniek J, Rizzi M, Miething C, Köhler N, Duyster J, Menssen HD, Boerries M, Buescher JM, Cabezas-Wallscheid N, Blazar BR, Apostolova P, Vago L, Pearce EL, Becher B, Zeiser R, (2022).
  Blood 2022, 140, 1167-1181
• 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, for the REACH3 Investigators. (2021)
  N Eng J Med 2021, 385, 228-238
• Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia.
  El Khawanky, N., Hughes A, Yu W, Myburgh R, Matschulla T, Taromi S, Aumann K, Clarson J, Vinnakota JM, Shoumariyeh K, Miething C, Lopez AF, Brown MP, Duyster J, Hein L, Manz MG, Hughes TP, White DL, Yong ASM, Zeiser R, (2021).
  Nat Commun. 2021, 12, 6436
• Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans.
  Uhl, F.M., 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).
  Science translational medicine 2020, 12, eabb8969.
• Ruxolitinib for Steroid-Refractory Acute Graft-Versus-Host Disease.
  Zeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, Szer J, Wagner EM, Zuckerman T, Mahuzier B, Xu J, Wilke C, Gandhi KK, Socié G; REACH2 Trial Group (2020).
  New England Journal of Medicine 2020, 382:1800-1810
• 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).
  Science Translational Medicine 10 (429), 2018.
• 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).
  Nature Medicine 24: 282-291, 2018.
• Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance GvHD via tissue damage.
  Schwab L*, Goroncy*, L, S. Palaniyandi S, S. Gautam, A. Triantafyllopoulou, A. Mocsai, W. Reichardt, F.J. Karlsson, S.V. Radhakrishnan, K. Hanke, A. Schmitt-Gräff, M. Freudenberg, F.D. von Loewenich, P. Wolf, F. Leonhardt, N. Baxan, D. Pfeifer, O. Schmah, A. Schönle, S.F. Martin, R. Mertelsmann, J. Duyster, J. Finke, M. Prinz, P. Henneke, H. Häcker, Hildebrandt, G.C., Häcker* G.*, Zeiser R* (2014).
  Nature Medicine 20: 648-54, 2014.
• The Nlrp3 inflammasome regulates acute graft-versus-host disease.
  Jankovic D, Ganesan J, Bscheider M, Stickel N, Weber FC, Guarda G, Follo M, Pfeifer D, Tardivel A, Ludigs K, Bouazzaoui A, Kerl K, Fischer JC, Haas T, Schmitt-Gräff A, Manoharan A, Müller L, Finke J, Martin SF, Gorka O, Peschel C, Ruland J, Idzko M, Duyster J, Holler E, French LE, *Poeck H, *Contassot E, *Zeiser R. (2013)
  J Exp Med 210, 1899-1910, 2013.
• 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 *contributed equally (2010).
  Nature Medicine 12, 1434-1438, 2010.