Abstract
The activated B-cell diffuse large B-cell-like lymphoma (ABC-DLBCL) correlates with poor prognosis. The B-cell receptor signaling pathway is known to be dysregulated in NHL/CLL and given BTK is a downstream mediator of BCR signaling, BTK constitutes an interesting and obvious therapeutic target. Given the high potency and selectivity of the BTK inhibitor, ONO/GS-4059, it was hypothesized that, the anti-tumor activity of ONO/GS-4059 could be further enhanced by combining it with the anti-CD20 Abs, rituximab (RTX) or obinutuzumab (GA101). ONO/GS-4059 combined with GA101 or RTX was significantly better than the respective monotherapy with tumor growth inhibition (TGI) of 90% for the GA101 combination and 86% for the RTX combination. In contrast, ibrutinib (PCI-32765) combined with RTX did not result in improved efficacy compared with respective monotherapy. Taken together these data indicate that the combination of ONO/GS-4059 with rituximab and particularly obinutuzumab may be an effective treatment for ABC-DLBCL.
Keywords:
ABC-DLBCL; Bruton’s tyrosine kinase; obinutuzumab; rituximab.
MeSH terms
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Agammaglobulinaemia Tyrosine Kinase
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Animals
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Antibodies, Monoclonal, Humanized / administration & dosage
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Antibodies, Monoclonal, Humanized / pharmacology
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Cell Line, Tumor
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Cytotoxicity, Immunologic / drug effects
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Disease Models, Animal
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Drug Therapy, Combination
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Female
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Humans
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Imidazoles / administration & dosage
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Imidazoles / pharmacology
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Killer Cells, Natural / drug effects
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Lymphoma, Large B-Cell, Diffuse / drug therapy
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Lymphoma, Large B-Cell, Diffuse / immunology
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Lymphoma, Large B-Cell, Diffuse / metabolism*
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Lymphoma, Large B-Cell, Diffuse / pathology
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Mice
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Neoplasm Staging
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Protein Kinase Inhibitors / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Pyrimidines / administration & dosage
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Pyrimidines / pharmacology
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Rituximab / administration & dosage
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Rituximab / pharmacology
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Treatment Outcome
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal, Humanized
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Imidazoles
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Protein Kinase Inhibitors
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Pyrimidines
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Rituximab
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Protein-Tyrosine Kinases
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Agammaglobulinaemia Tyrosine Kinase
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BTK protein, human
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Btk protein, mouse
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emt protein-tyrosine kinase
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tirabrutinib
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obinutuzumab