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1.
Cancer Sci ; 111(9): 3327-3337, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32639651

ABSTRACT

Tirabrutinib is a second-generation Bruton's tyrosine kinase inhibitor with greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II study of tirabrutinib in patients with treatment-naïve (Cohort A) or with relapsed/refractory (Cohort B) Waldenström's macroglobulinemia (WM). Patients were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR; ≥ partial response). Secondary endpoints included overall response rate (ORR; ≥ minor response), time to major response (TTMR), progression-free survival (PFS), overall survival (OS), and safety. In total, 27 patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 96.2% had the MYD88L265P mutation. MRR and ORR were 88.9% and 96.3%, respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow-up of 6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug-related atrial fibrillation or hypertension. Although the follow-up duration was relatively short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI-173646).


Subject(s)
Imidazoles/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Waldenstrom Macroglobulinemia/drug therapy , Aged , Aged, 80 and over , Biomarkers , Female , Genotype , Humans , Imidazoles/administration & dosage , Imidazoles/adverse effects , Male , Middle Aged , Mutation , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Neoplasm Grading , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Receptors, CXCR4/genetics , Receptors, CXCR4/metabolism , Treatment Outcome , Waldenstrom Macroglobulinemia/diagnosis , Waldenstrom Macroglobulinemia/etiology
2.
J Immunol Methods ; 361(1-2): 21-30, 2010 Sep 30.
Article in English | MEDLINE | ID: mdl-20470779

ABSTRACT

High mobility group box protein 1 (HMGB1), a major non-histone protein, released from the cells induces dendritic cell (DC) maturation and Th1 polarization. While DNA immunization has become an attractive method for eliciting the production of antibodies (Abs) in animals injected with DNA encoding an antigen, the Ab responses induced by DNA immunization remain relatively weak. In this study, we investigated the release of an HMGB1-conjugated ovalbumin (HMGB1 OVA conjugate, HMGB1-OVA) from necrotic cells and the Ab responses to HMGB1-OVA following DNA immunization. HMGB1-OVA was released from 293T cells after induction of necrosis in vitro and from the muscle into the serum after DNA immunization followed by electroporation. DCs pulsed with the supernatant of necrotic 293T cells containing HMGB1-OVA induced DO11.10 CD4+ T cell proliferation and interferon-γ secretion more potently than DCs pulsed with the cell supernatant containing OVA. DNA immunization with an expression plasmid for HMGB1-OVA by intramuscular injection elicited enhanced Th1-type Ab responses to OVA. Moreover, DNA immunization with a plasmid vector for release-type HMGB1 mutant-conjugated OVA elicited an even stronger response than DNA immunization with wild-type HMGB1-OVA. HMGB1-based DNA immunization described here has the potential to enhance the immunogenicity of antigens and elicit stronger Th1-type Ab response.


Subject(s)
HMGB Proteins/immunology , Immunity, Humoral/immunology , Immunization/methods , Ovalbumin/immunology , Vaccines, DNA/immunology , Animals , Antibodies/blood , Cell Proliferation , Dendritic Cells/immunology , Female , HMGB Proteins/genetics , Interferon-gamma/analysis , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Confocal , Plasmids/genetics , Specific Pathogen-Free Organisms , Vaccines, DNA/genetics
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