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3 results on '"Carlos-Alberto Gomez-Roca"'

1. The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment

Author

Elizabeth L. Hardaker, Emilio Sanseviero, Ankur Karmokar, Devon Taylor, Marta Milo, Chrysis Michaloglou, Adina Hughes, Mimi Mai, Matthew King, Anisha Solanki, Lukasz Magiera, Ricardo Miragaia, Gozde Kar, Nathan Standifer, Michael Surace, Shaan Gill, Alison Peter, Sara Talbot, Sehmus Tohumeken, Henderson Fryer, Ali Mostafa, Kathy Mulgrew, Carolyn Lam, Scott Hoffmann, Daniel Sutton, Larissa Carnevalli, Fernando J. Calero-Nieto, Gemma N. Jones, Andrew J. Pierce, Zena Wilson, David Campbell, Lynet Nyoni, Carla P. Martins, Tamara Baker, Gilberto Serrano de Almeida, Zainab Ramlaoui, Abdel Bidar, Benjamin Phillips, Joseph Boland, Sonia Iyer, J. Carl Barrett, Arsene-Bienvenu Loembé, Serge Y. Fuchs, Umamaheswar Duvvuri, Pei-Jen Lou, Melonie A. Nance, Carlos Alberto Gomez Roca, Elaine Cadogan, Susan E. Critichlow, Steven Fawell, Mark Cobbold, Emma Dean, Viia Valge-Archer, Alan Lau, Dmitry I. Gabrilovich, and Simon T. Barry

Subjects
Science
Abstract

Abstract The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8+ T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8+ T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity.

Published
2024
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2. Nivolumab and Relatlimab in Patients With Advanced Melanoma That Had Progressed on Anti–Programmed Death-1/Programmed Death Ligand 1 Therapy: Results From the Phase I/IIa RELATIVITY-020 Trial

Author

Paolo Antonio Ascierto, Evan J. Lipson, Reinhard Dummer, James Larkin, Georgina V. Long, Rachel E. Sanborn, Vanna Chiarion-Sileni, Brigitte Dréno, Stéphane Dalle, Dirk Schadendorf, Margaret K. Callahan, Marta Nyakas, Victoria Atkinson, Carlos Alberto Gomez-Roca, Naoya Yamazaki, Hussein A. Tawbi, Naomey Sarkis, Deepti Warad, Sonia Dolfi, Priyam Mitra, Satyendra Suryawanshi, Jean-Jacques Grob, University of Zurich, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale [Naples, Italy] (INT-FGP), Johns Hopkins University (JHU), Universität Zürich [Zürich] = University of Zurich (UZH), The institute of cancer research [London], The University of Sydney, Providence Cancer Center, Veneto Institute of Oncology IOV-IRCCS [Padua, Italy], Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Memorial Sloan Kettering Cancer Center (MSKCC), Oslo University Hospital [Oslo], Greenslopes Private Hospital [QLD, Australia] (GPH), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Cancer Center Research Institute [Tokyo], The University of Texas M.D. Anderson Cancer Center [Houston], Bristol-Myers Squibb [Princeton], Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)

Subjects
Cancer Research, Oncology, [SDV]Life Sciences [q-bio], Medizin, 10177 Dermatology Clinic, 610 Medicine & health, 2730 Oncology, 1306 Cancer Research
Abstract

PURPOSE Nivolumab and relatlimab activity in advanced melanoma with prior progression on anti–programmed death-1/programmed death ligand 1 (PD-(L)1)-containing regimens is under investigation. RELATIVITY-047 demonstrated significantly improved progression-free survival (PFS) for nivolumab and relatlimab over nivolumab in previously untreated advanced melanoma. METHODS The phase I/IIa, open-label RELATIVITY-020 trial part D assessed efficacy and safety of nivolumab and relatlimab in advanced melanoma with progression during, or within 3 months of, 1 (D1) or ≥ 1 (D2) anti–PD-(L)1-containing regimens. Safety was a primary end point. Objective response rate (coprimary end point) and PFS by blinded independent central review (BICR) were assessed. RESULTS Five hundred eighteen patients (D1 = 354; D2 = 164) received nivolumab and relatlimab. Among evaluable patients, the objective response rate by BICR was 12.0% (95% CI, 8.8 to 15.8) in D1 (n = 351) and 9.2% (95% CI, 5.2 to 14.7) in D2 (n = 163). Responses appeared to be enriched among patients with tumors expressing programmed death ligand 1 or lymphocyte activation gene 3; however, responses were observed regardless of programmed death ligand 1 and lymphocyte activation gene 3 expression (1%). The median duration of response was not reached (95% CI, 12.9 to not reached) in D1 and 12.8 months (95% CI, 6.9 to 12.9) in D2. The median PFS by BICR was 2.1 months (95% CI, 1.9 to 3.5) in D1 and 3.2 months (95% CI, 1.9 to 3.6) in D2; the 6-month PFS rate was 29.1% (95% CI, 24.2 to 34.1) and 27.7% (95% CI, 20.5 to 35.4), respectively. The grade 3-4 treatment-related adverse event incidence was 15.0% in D1 and 12.8% in D2. One case of grade 3 myocarditis and no treatment-related deaths occurred across part D. CONCLUSION Nivolumab and relatlimab had a manageable safety profile and demonstrated durable clinical activity in a proportion of patients with heavily pretreated advanced melanoma with prior progression on anti–PD-(L)1-containing regimens. [Media: see text]

Published
2023

3. 589 Xevinapant plus nivolumab in patients with advanced solid tumors who progressed on prior anti–PD-1/PD-L1 treatment: results of a dose-optimization, exploratory phase 1b/2 trial

Author

Emiliano Calvo Aller, Glenn Hanna, Maria Vieito Villar, Caroline Even, Victor Moreno, Chul Kim, Shuchi Gulati, Daniel Morgensztern, Ana Acuna-Villaorduna, Philippe Cassier, Dennie Jones, Florilene Bouisset, Daniela Sahlender, Elisabeth Rouits, Dany Spaggiari, Lars Damstrup, and Carlos-Alberto Gomez-Roca

Published
2022

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