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Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

ABSTRACT: Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD+ leukemia cells. This synergized with the allogeneic CD8+ T cell response, leading to long-term survival in six mouse models of FLT3-ITD+ AML. Sorafenib-related IL-15 production caused an increase in CD8+CD107a+IFN-?+ T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD+ AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8+ T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.

SUBMITTER: Mathew NR

PROVIDER: S-EPMC6029618 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

Mathew Nimitha R NR Baumgartner Francis F Braun Lukas L O'Sullivan David D Thomas Simone S Waterhouse Miguel M Müller Tony A TA Hanke Kathrin K Taromi Sanaz S Apostolova Petya P Illert Anna L AL Melchinger Wolfgang W Duquesne Sandra S Schmitt-Graeff Annette A Osswald Lena L Yan Kai-Li KL Weber Arnim A Tugues Sonia S Spath Sabine S Pfeifer Dietmar D Follo Marie M Claus Rainer R Lübbert Michael M Rummelt Christoph C Bertz Hartmut H Wäsch Ralph R Haag Johanna J Schmidts Andrea A Schultheiss Michael M Bettinger Dominik D Thimme Robert R Ullrich Evelyn E Tanriver Yakup Y Vuong Giang Lam GL Arnold Renate R Hemmati Philipp P Wolf Dominik D Ditschkowski Markus M Jilg Cordula C Wilhelm Konrad K Leiber Christian C Gerull Sabine S Halter Jörg J Lengerke Claudia C Pabst Thomas T Schroeder Thomas T Kobbe Guido G Rösler Wolf W Doostkam Soroush S Meckel Stephan S Stabla Kathleen K Metzelder Stephan K SK Halbach Sebastian S Brummer Tilman T Hu Zehan Z Dengjel Joern J Hackanson Björn B Schmid Christoph C Holtick Udo U Scheid Christof C Spyridonidis Alexandros A Stölzel Friedrich F Ordemann Rainer R Müller Lutz P LP Sicre-de-Fontbrune Flore F Ihorst Gabriele G Kuball Jürgen J Ehlert Jan E JE Feger Daniel D Wagner Eva-Maria EM Cahn Jean-Yves JY Schnell Jacqueline J Kuchenbauer Florian F Bunjes Donald D Chakraverty Ronjon R Richardson Simon S Gill Saar S Kröger Nicolaus N Ayuk Francis F Vago Luca L Ciceri Fabio F Müller Antonia M AM Kondo Takeshi T Teshima Takanori T Klaeger Susan S Kuster Bernhard B Kim Dennis Dong Hwan DDH Weisdorf Daniel D van der Velden Walter W Dörfel Daniela D Bethge Wolfgang W Hilgendorf Inken I Hochhaus Andreas A Andrieux Geoffroy G Börries Melanie M Busch Hauke H Magenau John J Reddy Pavan P Labopin Myriam M Antin Joseph H JH Henden Andrea S AS Hill Geoffrey R GR Kennedy Glen A GA Bar Merav M Sarma Anita A McLornan Donal D Mufti Ghulam G Oran Betul B Rezvani Katayoun K Shah Omid O Negrin Robert S RS Nagler Arnon A Prinz Marco M Burchert Andreas A Neubauer Andreas A Beelen Dietrich D Mackensen Andreas A von Bubnoff Nikolas N Herr Wolfgang W Becher Burkhard B Socié Gerard G Caligiuri Michael A MA Ruggiero Eliana E Bonini Chiara C Häcker Georg G Duyster Justus J Finke Jürgen J Pearce Erika E Blazar Bruce R BR Zeiser Robert R

Nature medicine 20180212 3

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD<sup>+</sup> leukemia cells. This synergized with the allogeneic CD8<sup>+</sup> T cell response, leading to long-term surviva ...[more]

PMID: 29431743

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Project description:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.

Dataset Information

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

Publications

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells.

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