Clinical cancer research, 2017-02-01, Vol.23 (3), p.804-813
Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma.
TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by neuroblastoma patient blood and bone marrow plasmas in neuroblastoma cells was tested. The impact of galunisertib on TGFβ1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NOD-scid gamma (NSG) mice was determined.
Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors and the TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against neuroblastoma cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two neuroblastoma cell lines or a patient-derived xenograft.
Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors. Clin Cancer Res; 23(3); 804-13. ©2016 AACRSee related commentary by Zenarruzabeitia et al., p. 615.
Receptor, Transforming Growth Factor-beta Type I ; Receptors, Transforming Growth Factor beta - genetics ; Humans ; Neoplasm Proteins - physiology ; Male ; Neoplasm Proteins - antagonists & inhibitors ; Gene Expression Profiling ; Receptors, Transforming Growth Factor beta - physiology ; Smad2 Protein - antagonists & inhibitors ; Quinolines - pharmacology ; RNA, Messenger - biosynthesis ; Protein Processing, Post-Translational - drug effects ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Female ; Phosphorylation - drug effects ; Neuroblastoma - pathology ; Transforming Growth Factor beta1 - biosynthesis ; Pyrazoles - pharmacology ; Killer Cells, Natural - transplantation ; Specific Pathogen-Free Organisms ; Immunotherapy, Adoptive ; Protein-Serine-Threonine Kinases - physiology ; Antibodies, Monoclonal - pharmacology ; RNA, Messenger - genetics ; Protein-Serine-Threonine Kinases - genetics ; Smad2 Protein - metabolism ; Transforming Growth Factor beta1 - genetics ; Transforming Growth Factor beta1 - physiology ; Antineoplastic Agents, Immunological - pharmacology ; Drug Synergism ; Protein-Serine-Threonine Kinases - biosynthesis ; Xenograft Model Antitumor Assays ; Receptors, Transforming Growth Factor beta - biosynthesis ; Animals ; RNA, Neoplasm - biosynthesis ; Receptors, Transforming Growth Factor beta - antagonists & inhibitors ; Cell Line, Tumor ; RNA, Neoplasm - genetics ; Mice, Inbred NOD ; Mice ; Neuroblastoma - metabolism ; Cytotoxicity, Immunologic ; Index Medicus ; TGFβR1 inhibitor ; dinutuximab ; adoptive cell therapy ; galunisertib ; immunotherapy
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