3 results on '"Doucey, P."'
Search Results
2. Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis
- Author
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Barbara Rewerska, MD, Lawrence D. Sher, MD, Sady Alpizar, MD, Sylvia Pauser, MD, Grazyna Pulka, MD, Neelufar Mozaffarian, MD, PhD, Yacine Salhi, PhD, Camille Martinet, MS, Wafaa Jabert, MS, Girish Gudi, PhD, Vinu CA, MPharm, MSc, Sunitha GN, PhD, Julie Macoin, MSc, Victor Anstett, MS, Riccardo Turrini, PhD, Marie-Agnès Doucey, PhD, Stanislas Blein, PhD, Cyril Konto, MD, and Martina Machkova, MD
- Subjects
Atopic dermatitis ,anti-OX40 receptor ,humanized monoclonal antibody ,phase 2 ,telazorlimab ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: Telazorlimab is a humanized anti-OX40 monoclonal antibody being studied for treatment of T-cell–mediated diseases. Objective: This randomized, placebo-controlled, phase 2b dose-range finding study investigated efficacy, safety, pharmacokinetics, and immunogenicity of telazorlimab in subjects with atopic dermatitis. Methods: In this 2-part study (NCT03568162), adults (≥18 years) with moderate-to-severe disease were randomized to various regimens of subcutaneous telazorlimab or placebo for 16 weeks’ blinded treatment, followed by 38 weeks’ open-label treatment and 12 weeks’ drug-free follow-up. Telazorlimab treatment groups (following a loading dose) in part 1 were 300 mg every 2 weeks; 300 mg every 4 weeks; or 75 mg every 4 weeks. Part 2 evaluated telazorlimab 600 mg every 2 weeks. The primary end point was percentage change from baseline in Eczema Area and Severity Index (EASI) at week 16. Safety assessments included incidence of treatment-emergent adverse events. Results: The study randomized 313 subjects in part 1 and 149 in part 2. At 16 weeks, the least squares mean percentage change from baseline in EASI was significantly greater in subjects receiving telazorlimab 300 mg every 2 weeks (part 1) and 600 mg every 2 weeks (part 2) versus placebo (−54.4% vs −34.2% for part 1 and −59.0% vs −41.8% for part 2, P = .008 for both). Telazorlimab was well tolerated, with similar distribution of adverse events between telazorlimab- and placebo-treated subjects in both part 1 and part 2. Conclusion: Telazorlimab, administered subcutaneously at 300 mg every 2 weeks or 600 mg every 2 weeks following a loading dose, was well tolerated and induced significant and progressive clinical improvement in adults with moderate-to-severe atopic dermatitis.
- Published
- 2024
- Full Text
- View/download PDF
3. PGE2inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function
- Author
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Morotti, Matteo, Grimm, Alizee J., Hope, Helen Carrasco, Arnaud, Marion, Desbuisson, Mathieu, Rayroux, Nicolas, Barras, David, Masid, Maria, Murgues, Baptiste, Chap, Bovannak S., Ongaro, Marco, Rota, Ioanna A., Ronet, Catherine, Minasyan, Aspram, Chiffelle, Johanna, Lacher, Sebastian B., Bobisse, Sara, Murgues, Clément, Ghisoni, Eleonora, Ouchen, Khaoula, Bou Mjahed, Ribal, Benedetti, Fabrizio, Abdellaoui, Naoill, Turrini, Riccardo, Gannon, Philippe O., Zaman, Khalil, Mathevet, Patrice, Lelievre, Loic, Crespo, Isaac, Conrad, Marcus, Verdeil, Gregory, Kandalaft, Lana E., Dagher, Julien, Corria-Osorio, Jesus, Doucey, Marie-Agnes, Ho, Ping-Chih, Harari, Alexandre, Vannini, Nicola, Böttcher, Jan P., Dangaj Laniti, Denarda, and Coukos, George
- Abstract
Expansion of antigen-experienced CD8+T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+TILs via the PGE2receptors EP2 and EP4. Mechanistically, PGE2inhibits IL-2 sensing in TILs by downregulating the IL-2Rγcchain, resulting in defective assembly of IL-2Rβ–IL2Rγcmembrane dimers. This results in impaired IL-2–mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.
- Published
- 2024
- Full Text
- View/download PDF
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