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

Nimitha R. Mathew; Francis Baumgartner; Lukas Braun; David O'Sullivan; Simone Thomas; Miguel Waterhouse; Tony A. Müller; Kathrin Hanke; Sanaz Taromi; Petya Apostolova; Anna L. Illert; Wolfgang Melchinger; Sandra Duquesne; Annette Schmitt-Graeff; Lena Osswald; Kai Li Yan; Arnim Weber; Sonia Tugues; Sabine Spath; Dietmar Pfeifer; Marie Follo; Rainer Claus; Michael Lübbert; Christoph Rummelt; Hartmut Bertz; Ralph Wäsch; Johanna Haag; Andrea Schmidts; Michael Schultheiss; Dominik Bettinger; Robert Thimme; Evelyn Ullrich; Yakup Tanriver; Giang Lam Vuong; Renate Arnold; Philipp Hemmati; Dominik Wolf; Markus Ditschkowski; Cordula Jilg; Konrad Wilhelm; Christian Leiber; Sabine Gerull; Jörg Halter; Claudia Lengerke; Thomas Pabst; Thomas Schroeder; Guido Kobbe; Wolf Rösler; Soroush Doostkam; Stephan Meckel; Kathleen Stabla; Stephan K. Metzelder; Sebastian Halbach; Tilman Brummer; Zehan Hu; Joern Dengjel; Björn Hackanson; Christoph Schmid; Udo Holtick; Christof Scheid; Alexandros Spyridonidis; Friedrich Stölzel; Rainer Ordemann; Lutz P. Müller; Flore Sicre-De-Fontbrune; Gabriele Ihorst; Jürgen Kuball; Jan E. Ehlert; Daniel Feger; Eva Maria Wagner; Jean Yves Cahn; Jacqueline Schnell; Florian Kuchenbauer; Donald Bunjes; Ronjon Chakraverty; Simon Richardson; Saar Gill; Nicolaus Kröger; Francis Ayuk; Luca Vago; Fabio Ciceri; Antonia M. Müller; Takeshi Kondo; Takanori Teshima; Susan Klaeger; Bernhard Kuster; Dennis H. Kim; Daniel Weisdorf; Walter Van Der Velden; Daniela Dörfel; Wolfgang Bethge; Inken Hilgendorf; Andreas Hochhaus; Geoffroy Andrieux; Melanie Börries; Hauke Busch; John Magenau; Pavan Reddy; Myriam Labopin; Joseph H. Antin; Andrea S. Henden; Geoffrey R. Hill; Glen A. Kennedy; Merav Bar; Anita Sarma; Donal McLornan; Ghulam Mufti; Betul Oran; Katayoun Rezvani; Omid Shah; Robert S. Negrin; Arnon Nagler; Marco Prinz; Andreas Burchert; Andreas Neubauer; Dietrich Beelen; Andreas Mackensen; Nikolas Von Bubnoff; Wolfgang Herr; Burkhard Becher; Gerard Socié; Michael A. Caligiuri; Eliana Ruggiero; Chiara Bonini; Georg Häcker; Justus Duyster; Jürgen Finke; Erika Pearce; Bruce R. Blazar; Robert Zeiser

doi:10.1038/nm.4484

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

Nimitha R. Mathew, Francis Baumgartner, Lukas Braun, David O'Sullivan, Simone Thomas, Miguel Waterhouse, Tony A. Müller, Kathrin Hanke, Sanaz Taromi, Petya Apostolova, Anna L. Illert, Wolfgang Melchinger, Sandra Duquesne, Annette Schmitt-Graeff, Lena Osswald, Kai Li Yan, Arnim Weber, Sonia Tugues, Sabine Spath, Dietmar PfeiferMarie Follo, Rainer Claus, Michael Lübbert, Christoph Rummelt, Hartmut Bertz, Ralph Wäsch, Johanna Haag, Andrea Schmidts, Michael Schultheiss, Dominik Bettinger, Robert Thimme, Evelyn Ullrich, Yakup Tanriver, Giang Lam Vuong, Renate Arnold, Philipp Hemmati, Dominik Wolf, Markus Ditschkowski, Cordula Jilg, Konrad Wilhelm, Christian Leiber, Sabine Gerull, Jörg Halter, Claudia Lengerke, Thomas Pabst, Thomas Schroeder, Guido Kobbe, Wolf Rösler, Soroush Doostkam, Stephan Meckel, Kathleen Stabla, Stephan K. Metzelder, Sebastian Halbach, Tilman Brummer, Zehan Hu, Joern Dengjel, Björn Hackanson, Christoph Schmid, Udo Holtick, Christof Scheid, Alexandros Spyridonidis, Friedrich Stölzel, Rainer Ordemann, Lutz P. Müller, Flore Sicre-De-Fontbrune, Gabriele Ihorst, Jürgen Kuball, Jan E. Ehlert, Daniel Feger, Eva Maria Wagner, Jean Yves Cahn, Jacqueline Schnell, Florian Kuchenbauer, Donald Bunjes, Ronjon Chakraverty, Simon Richardson, Saar Gill, Nicolaus Kröger, Francis Ayuk, Luca Vago, Fabio Ciceri, Antonia M. Müller, Takeshi Kondo, Takanori Teshima, Susan Klaeger, Bernhard Kuster, Dennis H. Kim, Daniel Weisdorf, Walter Van Der Velden, Daniela Dörfel, Wolfgang Bethge, Inken Hilgendorf, Andreas Hochhaus, Geoffroy Andrieux, Melanie Börries, Hauke Busch, John Magenau, Pavan Reddy, Myriam Labopin, Joseph H. Antin, Andrea S. Henden, Geoffrey R. Hill, Glen A. Kennedy, Merav Bar, Anita Sarma, Donal McLornan, Ghulam Mufti, Betul Oran, Katayoun Rezvani, Omid Shah, Robert S. Negrin, Arnon Nagler, Marco Prinz, Andreas Burchert, Andreas Neubauer, Dietrich Beelen, Andreas Mackensen, Nikolas Von Bubnoff, Wolfgang Herr, Burkhard Becher, Gerard Socié, Michael A. Caligiuri, Eliana Ruggiero, Chiara Bonini, Georg Häcker, Justus Duyster, Jürgen Finke, Erika Pearce, Bruce R. Blazar, Robert Zeiser

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201 Scopus citations

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-3 + 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.

Original language	English (US)
Pages (from-to)	282-291
Number of pages	10
Journal	Nature Medicine
Volume	24
Issue number	3
DOIs	https://doi.org/10.1038/nm.4484
State	Published - Mar 1 2018

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© 2018 Nature America, Inc., part of Springer Nature. All rights reserved.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029618

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Mathew, N. R., Baumgartner, F., Braun, L., O'Sullivan, D., Thomas, S., Waterhouse, M., Müller, T. A., Hanke, K., Taromi, S., Apostolova, P., Illert, A. L., Melchinger, W., Duquesne, S., Schmitt-Graeff, A., Osswald, L., Yan, K. L., Weber, A., Tugues, S., Spath, S., ... Zeiser, R. (2018). Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells. Nature Medicine, 24(3), 282-291. https://doi.org/10.1038/nm.4484

Mathew, NR, Baumgartner, F, Braun, L, O'Sullivan, D, Thomas, S, Waterhouse, M, Müller, TA, Hanke, K, Taromi, S, Apostolova, P, Illert, AL, Melchinger, W, Duquesne, S, Schmitt-Graeff, A, Osswald, L, Yan, KL, 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, D, 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, R, Müller, LP, Sicre-De-Fontbrune, F, Ihorst, G, Kuball, J, Ehlert, JE, Feger, D, Wagner, EM, 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, DH, 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, Antin, JH, Henden, AS, Hill, GR, Kennedy, GA, Bar, M, Sarma, A, McLornan, D, Mufti, G, Oran, B, Rezvani, K, Shah, 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, 'Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells', Nature Medicine, vol. 24, no. 3, pp. 282-291. https://doi.org/10.1038/nm.4484

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title = "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-3 + 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.",

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AU - O'Sullivan, David

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AU - Waterhouse, Miguel

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AU - Tugues, Sonia

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AU - Pfeifer, Dietmar

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AU - Claus, Rainer

AU - Lübbert, Michael

AU - Rummelt, Christoph

AU - Bertz, Hartmut

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AU - Haag, Johanna

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AU - Schultheiss, Michael

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AU - Klaeger, Susan

AU - Kuster, Bernhard

AU - Kim, Dennis H.

AU - Weisdorf, Daniel

AU - Van Der Velden, Walter

AU - Dörfel, Daniela

AU - Bethge, Wolfgang

AU - Hilgendorf, Inken

AU - Hochhaus, Andreas

AU - Andrieux, Geoffroy

AU - Börries, Melanie

AU - Busch, Hauke

AU - Magenau, John

AU - Reddy, Pavan

AU - Labopin, Myriam

AU - Antin, Joseph H.

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AU - Kennedy, Glen A.

AU - Bar, Merav

AU - Sarma, Anita

AU - McLornan, Donal

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AU - Oran, Betul

AU - Rezvani, Katayoun

AU - Shah, Omid

AU - Negrin, Robert S.

AU - Nagler, Arnon

AU - Prinz, Marco

AU - Burchert, Andreas

AU - Neubauer, Andreas

AU - Beelen, Dietrich

AU - Mackensen, Andreas

AU - Von Bubnoff, Nikolas

AU - Herr, Wolfgang

AU - Becher, Burkhard

AU - Socié, Gerard

AU - Caligiuri, Michael A.

AU - Ruggiero, Eliana

AU - Bonini, Chiara

AU - Häcker, Georg

AU - Duyster, Justus

AU - Finke, Jürgen

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AU - Blazar, Bruce R.

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N2 - 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-3 + 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.

AB - 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-3 + 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.

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

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