20 research outputs found

    Exercise induces dynamic changes in intra-articular metabolism and inflammation associated with remodeling of the infrapatellar fat pad in mice

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    Abstract We hypothesized that daily exercise promotes joint health by upregulating anti-inflammatory mediators via adaptive molecular and metabolic changes in the infrapatellar fat pad (IFP). We tested this hypothesis by conducting time-resolved analyses between 1 and 14 days of voluntary wheel running exercise in C57BL/6J mice. IFP structure and cellularity were evaluated by histomorphology, picrosirius red collagen staining, and flow cytometry analysis of stromal vascular fraction cells. Joint inflammation and metabolism were evaluated by multiplex gene expression analysis of synovium-IFP tissue and synovial fluid metabolomics, respectively. Exercise transiently increased cytokine and chemokine gene expression in synovium-IFP tissue, resolving within the first 5 days of exercise. The acute inflammatory response was associated with decreased adipocyte size and elevated CD45+Gr1+ myeloid cells, increased collagen content, and oxidized phospholipids. Exercise acutely altered synovial fluid metabolites, characterized by increased amino acids, peptides, bile acids, sphingolipids, dicarboxylic acids, and straight medium chain fatty acids and decreased hydroxy fatty acids and diacylglycerols. Between 5 and 14 days of exercise, inflammation, collagen, and adipocyte size returned to pre-exercise levels, and CD206+ immuno-regulatory macrophages increased. Thus, although the onset of new daily exercise transiently induced synovium-IFP inflammation and altered tissue structure, sustained daily exercise promoted IFP homeostasis

    Anti-CCR4 Monoclonal Antibody, Mogamulizumab, Demonstrates Significant Improvement in PFS Compared to Vorinostat in Patients with Previously Treated Cutaneous T-Cell Lymphoma (CTCL): Results from the Phase III MAVORIC Study

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    Abstract Introduction: Cutaneous T- cell lymphoma (CTCL) is a rare form of non-Hodgkin lymphoma. Patients with CTCL suffer reduced quality of life from intractable itching and recurrent infections. Advanced stages have a poor prognosis. Mogamulizumab (Moga) is a monoclonal antibody directed against chemokine receptor 4 (CCR4), which is overexpressed on malignant T-cells. In a Phase I-II study in CTCL, Moga demonstrated a tolerable safety profile with a 37% overall response rate (ORR). Based on these results, MAVORIC [NCT01728805], an open-label, multinational, randomized, Phase III study, was initiated to compare Moga to vorinostat (Vor) in previously treated CTCL. This study is the largest randomized trial and the first pivotal trial to use progression-free survival (PFS) as a primary endpoint in CTCL. Methods: Adult patients with histologically confirmed mycosis fungoides (MF) or Sézary syndrome (SS) who had failed ≥1 systemic therapy were enrolled, stratified by disease type (MF or SS) and stage (IB/II or III/IV), and randomized 1:1 to Moga 1.0 mg/kg (weekly for the first 4-week cycle and then every 2 weeks) or Vor (400 mg daily). Patients randomized to Vor could crossover to Moga upon progression or intolerable toxicity. The primary endpoint was investigator-assessed PFS in the randomized population using the global composite response (based on skin, blood, nodes and viscera) according to the ISCL/EORTC consensus guidelines. Sample size was calculated to provide 90% power to detect a 50% improvement in PFS. Key secondary endpoints included ORR, duration of response (DOR) and quality of life (QoL). Results: A total of 372 patients were randomized (Intent-to-Treat population) and had the following characteristics (Moga vs Vor): median age 63.5 yrs (25-101) vs 65.0 yrs (25-89); ECOG-PS 0-1, 184 (99%) vs 186 (100%); ECOG-PS 2, 2 (1%) vs 0; stage IB/IIA, 36 (19.4%) vs 49 (26.3%); stage IIB, 32 (17.2%) vs 23 (12.4%); stage III/IV, 118 (63.4%) vs 114 (61.3%); MF, 105 (56.5%) vs 99 (53.2%); SS, 81 (43.5%) vs 87 (46.8%). The median number of prior systemic treatments for both the Moga and Vor arms was 3. According to investigator assessment, treatment with Moga resulted in a significant improvement in PFS compared to Vor (HR 0.53 [95% CI: 0.41, 0.69], p&amp;lt;0.0001) with a median PFS of 7.7 months (95% CI: 5.7, 10.3) for Moga and 3.1 months (95% CI: 2.9, 4.1) for Vor (Figure 1). Improvement in PFS was also demonstrated based on independent review (HR 0.64 [95% CI: 0.49, 0.84], p=0.0007): 6.7 months for Moga and 3.8 months for Vor. Moga was associated with superior PFS in predefined subgroups (Figure 2). Global ORR was significantly improved in the patients randomized to Moga at 28.0% vs 4.8% for Vor (p&amp;lt;0.0001). ORR in predefined subgroups, DOR and response by disease compartment all favored Moga vs Vor (Table 1). Significant improvement in ORR was found with Moga vs Vor in patients with both MF (21.0% vs 7.1%, respectively; p=0.0042) and SS (37.0% vs 2.3%, respectively; p&amp;lt;0.0001). An ORR of 30.1% was observed in Moga treated patients who crossed over from Vor. Patient-reported outcomes, as measured by the Skindex-29 and FACT-G, showed significantly greater symptom reduction and improved functional status in favor of Moga vs Vor in early cycles and throughout treatment (p&amp;lt;0.05). The median dose intensity for Moga was 97.5% vs 95.7% for Vor, supporting adequate treatment in both arms. Treatment exposure was longer with Moga (median 170 vs 84 days for Vor). The most common treatment-emergent adverse events (TEAEs; &amp;gt;20%) that were more frequent (&amp;gt;15% difference) in the Moga vs Vor arm included infusion-related reactions (33.2% vs 0.5%, respectively) and skin eruptions due to drug (23.9% vs 0.5%, respectively). The majority of TEAEs with Moga were mild to moderate in severity (grade I/II, 54.9%; grade III/IV/V, 42.4%). Common TEAEs reported more often with Vor vs Moga included diarrhea (61.8% vs 23.4%), nausea (42.5% vs 15.2%), thrombocytopenia (30.6% vs 11.4%), dysgeusia (29.0% vs 3.3%), and increased blood creatinine (28.0% vs 3.3%). Conclusions: In this first report of a randomized Phase III study evaluating PFS as primary endpoint in CTCL, Moga, a novel CCR4-targeting antibody therapy, demonstrated significantly superior PFS, ORR, and QoL compared to Vor in patients with previously treated CTCL. The safety profile was consistent with previous reports. This study supports Moga as a valuable new therapeutic option in patients with CTCL. Disclosures Kim: Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Soligenix: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy, Research Funding; Neumedicine: Research Funding; miRagen: Research Funding; Merck: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin-Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Bagot: Innate Pharma: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Kyowa: Membership on an entity's Board of Directors or advisory committees. Horwitz: Kyowa-Hakka-Kirin: Consultancy, Research Funding; Mundipharma: Consultancy; ADCT Therapeutics: Research Funding; Forty-Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; HUYA: Consultancy; Millenium/Takeda: Consultancy, Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron Therapeutics: Research Funding. Whittaker: Celgene: Honoraria; Galderma: Research Funding. Vermeer: Innate Pharma safety board for IPH4102-101: Membership on an entity's Board of Directors or advisory committees. Zinzani: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; J&amp;J: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sokol: Spectrum Pharmaceuticals: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy. Kim: Kyowa Kirin Pharmaceutical Development, Inc.: Other: Clinical trials investigator; Solgenix: Other: Clinical trials investigator; Actelion: Consultancy; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; US Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy. Ortiz-Romero: ACTELION: Consultancy; 4SC: Consultancy; Innate Pharma: Consultancy; Takeda: Consultancy; MEDA: Research Funding. Eradat: Abbvie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Scarisbrick: 4SC: Consultancy; Takeda: Consultancy; Mallinckrodt: Consultancy; Innate Pharma: Consultancy; Actelion: Consultancy. Elmets: NCI: Research Funding; Veterans Administration: Research Funding; California Wine Grape Assn: Research Funding; Solegenix: Research Funding; Idera: Research Funding; Elorac: Research Funding; Ferndale Labs: Consultancy, Research Funding; Astellas Pharma: Research Funding. Dalle: Kyowa Hakko Kirin Pharmaceutical: Research Funding. Fisher: Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Halwani: Amgen: Research Funding; Pharmacyclics: Research Funding; Takeda: Research Funding; Genetech Inc.: Research Funding; Roche/Genentech Inc.: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squib: Research Funding; Kyowa Hikko Kirin: Research Funding; AbbVie: Research Funding; Immune Design: Research Funding; Miragen: Research Funding. Poligone: Actelion Pharmaceutical: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy; Kyowa Hakko Kirin: Research Funding; Soligenix: Research Funding. Khot: Celgene: Consultancy; Janssen: Consultancy; Amgen: Other: Travel Grant. Moskowitz: Incyte: Research Funding; Takeda: Honoraria; Bristol Myers-Squibb: Consultancy, Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Honoraria, Research Funding. Dwyer: Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Moriya: Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Humphrey: KYOWA KYRIN PHARMACEUTICAL DEVELOPMENT: Employment. Hudgens: Clinical Outcomes Solutions: Consultancy, Research Funding. Grebennik: Kyowa Kirin Pharmaceutical Development, Inc.: Employment. Tobinai: AbbVie: Research Funding; Chugai: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Janssen: Honoraria, Research Funding; HUYA Bioscience: Honoraria; Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; Mundipharma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding. Duvic: MDACC: Other: Safety Oversight Committee, Research Funding. </jats:sec
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