Midostaurin abrogates CD33‐directed UniCAR and CD33‐CD3 bispecific antibody therapy in acute myeloid leukaemia

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.

[1]  Anja Feldmann,et al.  Adaptor CAR Platforms—Next Generation of T Cell-Based Cancer Immunotherapy , 2020, Cancers.

[2]  E. E. Garling,et al.  The Bruton’s tyrosine kinase inhibitor ibrutinib abrogates bispecific antibody‐mediated T‐cell cytotoxicity , 2020, British journal of haematology.

[3]  G. Egan,et al.  UniCAR T cell immunotherapy enables efficient elimination of radioresistant cancer cells , 2020, Oncoimmunology.

[4]  Michel Sadelain,et al.  Chimeric Antigen Receptor Therapy. , 2018, The New England journal of medicine.

[5]  R. Larson,et al.  Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. , 2018, Blood advances.

[6]  M. Caligiuri,et al.  Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells , 2018, Nature Medicine.

[7]  H. Einsele,et al.  CAR T-cells targeting FLT3 have potent activity against FLT3−ITD+ AML and act synergistically with the FLT3-inhibitor crenolanib , 2018, Leukemia.

[8]  W. Hiddemann,et al.  Tyrosine kinase inhibition increases the cell surface localization of FLT3-ITD and enhances FLT3-directed immunotherapy of acute myeloid leukemia , 2017, Leukemia.

[9]  W. Hiddemann,et al.  Midostaurin Reduces Bite® Mediated Cytotoxicity Against Acute Myeloid Leukemia , 2017 .

[10]  H. Einsele,et al.  CAR T Cells Targeting FLT3 on AML Confer Potent Anti-Leukemic Activity and Act Synergistically with the FLT3 Inhibitor Midostaurin , 2017 .

[11]  W. Klapper,et al.  Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia , 2017, The New England journal of medicine.

[12]  J. Cortes,et al.  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) , 2016 .

[13]  R. Schlenk,et al.  How I treat refractory and early relapsed acute myeloid leukemia. , 2015, Blood.

[14]  G. Ehninger,et al.  Flexible Antigen-Specific Redirection of Human Regulatory T Cells Via a Novel Universal Chimeric Antigen Receptor System , 2014 .

[15]  B. Isermann,et al.  Clinically relevant doses of FLT3-kinase inhibitors quizartinib and midostaurin do not impair T-cell reactivity and function , 2014, Haematologica.

[16]  G. Ehninger,et al.  Redirection of T cells with a first fully humanized bispecific CD33–CD3 antibody efficiently eliminates AML blasts without harming hematopoietic stem cells , 2013, Leukemia.

[17]  C. Schiffer,et al.  Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia , 2012, Leukemia.

[18]  A. Jankowska,et al.  Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. , 2008, Blood.