Midostaurin abrogates CD33-directed UniCAR and CD33-CD3 bispecific antibody therapy in acute myeloid leukaemia
Frederick Fasslrinner
Medical Clinic and Polyclinic I, University Hospital ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
FF and CA contributed equally to this work.Search for more papers by this authorClaudia Arndt
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
FF and CA contributed equally to this work.Search for more papers by this authorStefanie Koristka
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
Search for more papers by this authorAnja Feldmann
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
Search for more papers by this authorHeidi Altmann
Medical Clinic and Polyclinic I, University Hospital ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
Search for more papers by this authorMalte von Bonin
Medical Clinic and Polyclinic I, University Hospital ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorMarc Schmitz
Institute of Immunology, Medical Faculty ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
Centre for Regenerative Therapies Dresden, ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
University Cancer Centre (UCC), ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorMartin Bornhäuser
Medical Clinic and Polyclinic I, University Hospital ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
Centre for Regenerative Therapies Dresden, ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
University Cancer Centre (UCC), ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Michael Bachmann
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
Centre for Regenerative Therapies Dresden, ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
University Cancer Centre (UCC), ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Centre (DKFZ), Heidelberg, Germany
Correspondence: Michael Bachmann, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany.
E-mail: [email protected]
Search for more papers by this authorFrederick Fasslrinner
Medical Clinic and Polyclinic I, University Hospital ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
FF and CA contributed equally to this work.Search for more papers by this authorClaudia Arndt
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
FF and CA contributed equally to this work.Search for more papers by this authorStefanie Koristka
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
Search for more papers by this authorAnja Feldmann
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
Search for more papers by this authorHeidi Altmann
Medical Clinic and Polyclinic I, University Hospital ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
Search for more papers by this authorMalte von Bonin
Medical Clinic and Polyclinic I, University Hospital ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorMarc Schmitz
Institute of Immunology, Medical Faculty ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
Centre for Regenerative Therapies Dresden, ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
University Cancer Centre (UCC), ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorMartin Bornhäuser
Medical Clinic and Polyclinic I, University Hospital ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
Centre for Regenerative Therapies Dresden, ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
University Cancer Centre (UCC), ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Centre (DKFZ), Heidelberg, Germany
Search for more papers by this authorCorresponding Author
Michael Bachmann
Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Dresden, Germany
Centre for Regenerative Therapies Dresden, ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
University Cancer Centre (UCC), ‘Carl Gustav Carus’, TU Dresden, Dresden, Germany
German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Centre (DKFZ), Heidelberg, Germany
Correspondence: Michael Bachmann, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstraße 400, 01328 Dresden, Germany.
E-mail: [email protected]
Search for more papers by this authorSummary
Combinatory therapeutic approaches of different targeted therapies in acute myeloid leukaemia are currently under preclinical/early clinical investigation. To enhance anti-tumour effects, we combined the tyrosine kinase inhibitor (TKI) midostaurin and T-cell mediated immunotherapy directed against CD33. Clinically relevant concentrations of midostaurin abrogated T-cell mediated cytotoxicity both after activation with bispecific antibodies and chimeric antigen receptor T cells. This information is of relevance for clinicians exploring T-cell mediated immunotherapy in early clinical trials. Given the profound inhibition of T-cell functionality and anti-tumour activity, we recommend specific FLT3 TKIs for further clinical testing of combinatory approaches with T-cell based immunotherapy.
Conflict of interest
Mi.B. holds patents related to the CD33-CD3 bsAb and the UniCAR system and is shareholder of Gemoab. The other authors declare to have no conflict of interest.
Supporting Information
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| bjh15975-sup-0001-supinfo.pptxapplication/mspowerpoint, 392.7 KB |
Fig S1. Dose-dependent effect of Midostaurin on the cytotoxic potential of CD33 TM-redirected UniCAR T cells and CD33-CD3 bsAb redirected Pan T cells. Fig S2. Patient characteristics of cryopreserved primary AML samples. Fig S3. Midostaurin inhibits activation and exhaustion of TM- and bsAb-redirected CD4+ and CD8+ UniCAR T cells in a prostate tumour model. Fig S4. Midostaurin inhibits perforin and granzyme B production of TM- and bsAb-redirected CD4+ and CD8+ UniCAR T cells in a prostate tumour model. Fig S5. Midostaurin blocks cytokine secretion of TM- and bsAb-redirected CD4+ and CD8+ UniCAR T cells in a prostate tumour model. Fig S6. Dose-dependent effect of Midostaurin on expansion and proliferation of CD33-redirected UniCAR T cells. Table SI. List of fluorochrome-labeled antibodies. Data S1. Supplementary methods. |
| bjh15975-sup-0001-SupInfo.docxWord document, 11.3 KB |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- Arndt, C., von Bonin, M., Cartellieri, M., Feldmann, A., Koristka, S., Michalk, I., Stamova, S., Bornhäuser, M., Schmitz, M., Ehninger, G. & Bachmann, M.P. (2013) Redirection of T cells with a first fully humanized bispecific CD33-CD3 antibody efficiently eliminates AML blasts without harming hematopoietic stem cells. Leukemia, 27, 964–967.
- Jetani, H., García-Cadenas, I., Nerreter, T., Rydzek, J., Thomas, S., Herr, W., Sierra, J., Bonig, H., Einsele, H. & Hudecek, M. (2017) CAR T cells targeting FLT3 on AML confer potent anti-leukemic activity and act synergistically with the FLT3 inhibitor midostaurin. Blood, 130, 1351 (abstract).
- Jetani, H., García-Cadenas, I., Nerreter, T., Thomas, S., Rydzek, J., Meijide, J.B., Bonig, H., Herr, W., Sierra, J., Einsele, H. & Hudecek, M. (2018) CAR T-cells targeting FLT3 have potent activity against FLT3-ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib. Leukemia, 32, 1168–1179.
- June, C.H. & Sadelain, M. (2018) Chimeric antigen receptor therapy. New England Journal of Medicine, 379, 64–73.
- Kantarjian, H., Stein, A., Gökbuget, N., Fielding, A.K., Schuh, A.C., Ribera, J.-M., Wie, A., Dombret, H., Foà, R., Bassan, R., Arslan, Ö., Sanz, M.A., Bergeron, J., Demirkan, F., Lech-Maranda, E., Rambaldi, A., Thomas, X., Horst, H.-A., Brüggemann, M., Klapper, W., Wood, B.L., Fleishman, A., Nagorsen, D., Holland, C., Zimmerman, Z. & Topp, M.S. (2017) Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. New England Journal of Medicine, 376, 836–847.
- Koristka, S., Cartellieri, M., Feldmann, A., Arndt, C., Loff, S., Michalk, I., Aliperta, R., von Bonin, M., Bornhäuser, M., Ehninger, A., Ehninger, G. & Bachmann, M.P. (2014) Flexible antigen-specific redirection of human regulatory T cells via a novel universal chimeric antigen receptor system. Blood, 124, 3494 (abstract).
- Levis, M.J., Cortes, J.E., Gammon, G.M., Trone, D., Kang, D. & Li, J.( 2016) Laboratory and clinical investigations to identify the optimal dosing strategy for quizartinib (AC220) monotherapy in FLT3-Itd-positive (+) relapsed/refractory (R/R) acute myeloid leukemia (AML). Blood, 128, 4042(abstract).
- Lindl, B., Krupka, C., Chapman- Arvedson, T., Kischel, R., Kufer, P., Haubner, S., Lichtenegger, F.S., Koehnke, T., Metzeler, K.H., Konstandin, N., Spiekermann, K., Hiddemann, W. & Subklewe, M. (2017) Midostaurin reduces Bite® mediated cytotoxicity against acute myeloid leukemia. Blood, 130, 2656 (abstract).
- 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., 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, G.L., 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, S.K., Halbach, S., Brummer, T., Hu, Z., Dengjel, J., Hackanson, B., Schmid, C., Holtick, U., Scheid, C., Spyridonidis, A., Stölzel, F., Ordemann, R., Müller, L.P., Sicre-de-Fontbrune, F., Ihorst, G., Kuball, J., Ehlert, J.E., Feger, D., Wagner, E.M., Cahn, J.Y., Schnell, J., Kuchenbauer, F., Bunjes, D., Chakraverty, R., Richardson, S., Gill, S., Kröger, N., Ayuk, F., Vago, L., Ciceri, F., Müller, A.M., Kondo, T., Teshima, T., Klaeger, S., Kuster, B., Kim, D.D.H., 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, J.H., Henden, A.S., Hill, G.R., Kennedy, G.A., Bar, M., Sarma, A., McLornan, D., Mufti, G., Oran, B., Rezvani, K., Shah, O., Negrin, R.S., Nagler, A., Prinz, M., Burchert, A., Neubauer, A., Beelen, D., Mackensen, A., von Bubnoff, N., Herr, W., Becher, B., Socié, G., Caligiuri, M.A., Ruggiero, E.,Bonini, C., Häcker, G., Duyster, J., Finke, J., Pearce, E., Blazar, B.R. & 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, 282–291.
- Reiter, K., Polzer, H., Krupka, C., Maiser, A., Vick, B., Rothenberg-Thurley, M., Metzeler, K.H., Dörfel, D., Salih, H.R., Jung, G., Nößner, E., Jeremias, I., Hiddemann, W., Leonhardt, H., Spiekermann, K., Subklewe, M. & Greif, P.A. (2018) Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia. Leukemia, 32, 313–322.
- Schade, A.E., Schieven, G.L., Townsend, R., Jankowska, A.M., Suslic, V., Zhang, R., Szpurka, H. & Maciejewski, J.P. (2008) Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood, 111, 1366–1377.
- Stone, R.M., Fischer, T., Paquette, R., Schiller, G., Schiffer, C.A., Ehninger, G., Cortes, J., Kantarjian, H.M., DeAngelo, D.J., Huntsman-Labed, A., Dutreix, C., del Corral, A. & Giles, F. (2012) Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia, 26, 2061–2068.
- Stone, R.M., Manley, P.W., Larson, R.A. & Capdeville, R. (2018) Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Advances, 2, 444–453.
- Thol, F., Schlenk, R.F., Heuser, M. & Ganser, A. (2015) How I treat refractory and early relapsed acute myeloid leukemia. Blood, 126, 319–327.
- Wolleschak, D., Mack, T.S., Perner, F., Frey, S., Schnöder, T.M., Wagner, M.C., Höding, C., Pils, M.C., Parkner, A., Klische, S., Schraven, B., Hebel, K., Brunner-Weinzierl, M., Isermann, B., Lipka, D.B. & Heidel, F.H. (2014) Clinically relevant doses of FLT3-kinase inhibitors quizartinib and midostaurin do not impair T-cell reactivity and function. Haematologica, 99, e90–e93.
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