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1 Publication
T Cell Based Immunotherapy of Acute Myeloid Leukemia is Abrogated by the Tyrosine Kinase Inhibitor Midostaurin
Fasslrinner, F.; Arndt, C.; Koristka, S.; Feldmann, A.; Altmann, H.; von Bonin, M.; Schmitz, M.; Bornhäuser, M.; Bachmann, M.;
Background
Induction chemotherapy is currently the standard of care for treatment of acute myeloid leukemia (AML) with 5-year disease-free survival of 33%. Given the large proportion of non-responders and relapsed patients, novel adjuvant drugs are urgently needed. Especially, targeted therapies including small molecules and T cell based immunotherapies are under intensive preclinical and clinical investigation. The tyrosine kinase inhibitor Midostaurin recently received approval for treatment of FLT3-positive AML. In addition to chemotherapy, it significantly deepens remission rates and improves overall survival of patients. In light of future combinatorial approaches, simultaneous application of different targeted therapies should theoretically augment anti-tumor effects.

Aims
Therefore, we questioned whether Midostaurin could strengthen cytotoxic effector mechanisms of redirected switchable UniCAR T cells or bispecific antibody-redirected T cells against primary AML cells.

Methods/Results
By performing in vitro co-cultivation assays with patient-derived AML cells, it was shown that Midostaurin concentrations ≥ 1 µM significantly impair the activation, proliferation, cytokine production and cytotoxicity of autologous and allogeneic T cells after engagement via bsAb or the UniCAR system. Data could be also verified in a solid tumor model.

Summary/Conclusion
At concentrations ranging between 0.1 and 10 M, it was shown that Midostaurin and its metabolites are indeed able to inhibit several components of the TCR signaling pathway including LcK, Zeta-chain-associated protein kinase 70 (ZAP-70), mitogen-activated protein kinase (MAPK) and Protein kinase C (PKC) in vitro. Therefore, we argue that the observed T cell inhibition by Midostaurin in our studies is caused by the inhibition of several of these kinases. This hypothesis is supported by the work of two individual research groups that were able to show synergistic effects by combining FLT3 selective TKIs with different T cell-based immunotherapies. Because Midostaurin through concentrations above ≥ 1 µM have been observed in earlier performed dose finding studies, we speculate that current standard Midostaurin therapy will inhibit T cell function in vivo.
In summary, our data underline that combination of Midostaurin and T cell-based immunotherapies in FLT3-positive AML patients is not recommended due to the suppressive effect of Midostaurin on T cells. Therefore, more selective TKI or other small molecules should be chosen to avoid impairment of T cell functions.
  • Poster
    1st European CAR T Cell Meeting, 14.-16.02.2019, Paris, France

Publ.-Id: 29139 - Permalink