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

Br J Haematol. 2019 Sep;186(5):735-740. doi: 10.1111/bjh.15975. Epub 2019 May 23.

Abstract

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.

Keywords: T-cell based immunotherapy; acute myeloid leukaemia; combinatory therapy; midostaurin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology
  • Sialic Acid Binding Ig-like Lectin 3 / metabolism*
  • Staurosporine / analogs & derivatives*
  • Staurosporine / pharmacology
  • Staurosporine / therapeutic use

Substances

  • Antineoplastic Agents
  • CD33 protein, human
  • Sialic Acid Binding Ig-like Lectin 3
  • Staurosporine
  • midostaurin