المؤلفون: Hardaker, Elizabeth L., Sanseviero, Emilio, Karmokar, Ankur, Taylor, Devon, Milo, Marta, Michaloglou, Chrysis, Hughes, Adina, Mai, Mimi, King, Matthew, Solanki, Anisha, Magiera, Lukasz, Miragaia, Ricardo, Kar, Gozde, Standifer, Nathan, Surace, Michael, Gill, Shaan, Peter, Alison, Talbot, Sara, Tohumeken, Sehmus, Fryer, Henderson

المصدر: Nature Communications; 2/24/2024, Vol. 15 Issue 1, p1-20, 20p

مصطلحات موضوعية: TUMOR microenvironment, IMMUNE checkpoint inhibitors, TYPE I interferons, MYELOID cells, ATAXIA telangiectasia, CYTOTOXIC T cells

مستخلص: 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. The ATR inhibitor ceralasertib has shown clinical activity in combination with immune-checkpoint inhibitors in several cancer types. Here the authors report the anti-tumor activity and the immunomodulatory changes, dependent on up-regulation of type I interferon pathway, following intermittent ATR inhibition in preclinical cancer models. [ABSTRACT FROM AUTHOR]

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المؤلفون: Kreitman, Robert, Dearden, Claire, Zinzani, Pier Luigi, Delgado, Julio, Karlin, Lionel, Robak, Tadeusz, Gladstone, Douglas, Le Coutre, Philipp, Dietrich, Sascha, Gotic, Mirjana, Larratt, Loree, Offner, Fritz, Schiller, Gary, Swords, Ronan, Bacon, Larry, Bocchia, Monica, Bouabdallah, Krimo, Breems, Dimitri, Cortelezzi, Agostino, Dinner, Shira, Doubek, Michael, Gjertsen, Bjørn Tore, Gobbi, Marco, Hellmann, Andrzej, Leprêtre, Stéphane, Maloisel, Frédéric, Ravandi, Farhad, Rousselot, Philipp, Rummel, Mathias, Siddiqi, Tanya, Tadmor, Tamar, Troussard, Xavier, Yi, Cecilia Arana, Saglio, Giuseppe, Roboz, Gail, Balic, Kemal, Standifer, Nathan, He, Peng, Marshall, Shannon, Wilson, Wyndham, Pastan, Ira, Yao, Nai-Shun, Giles, Francis

المساهمون: National Cancer Institute Bethesda (NCI-NIH), National Institutes of Health Bethesda, MD, USA (NIH), Royal Marsden NHS Foundation Trust, Alma Mater Studiorum Università di Bologna = University of Bologna (UNIBO), Barcelona Centre for International Health Research, Hospital Clinic (CRESIB), Universitat de Barcelona (UB), Service d’Hématologie Centre Hospitalier Lyon Sud - HCL, Centre Hospitalier Lyon Sud CHU - HCL (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Medical University of Łódź (MUL), Johns Hopkins University (JHU), Charité - UniversitätsMedizin = Charité - University Hospital Berlin, Universität Heidelberg Heidelberg = Heidelberg University, Clinical Center of Serbia (KCS), University of Alberta, Universiteit Gent = Ghent University (UGENT), David Geffen School of Medicine Los Angeles, University of California Los Angeles (UCLA), University of California (UC)-University of California (UC), University of Miami Coral Gables, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Università degli Studi di Siena = University of Siena (UNISI), CHU Bordeaux, Ziekenhuis Netwerk Antwerpen (ZNA), Università degli Studi di Milano = University of Milan (UNIMI), Feinberg School of Medicine, Northwestern University Evanston, Faculty of Science Brno (SCI / MUNI), Masaryk University Brno (MUNI), Haukeland University Hospital, University of Bergen (UiB), Ospedale Policlinico San Martino Genoa, Medical University of Gdańsk, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), Clinique Sainte Anne Strasbourg, MD Anderson Cancer Center Houston, The University of Texas Health Science Center at Houston (UTHealth), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), City of Hope National Medical Center, Bnai Zion Medical Center Israël, Hôpital Côte de Nacre CHU Caen, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), The University of New Mexico Albuquerque, Università degli studi di Torino = University of Turin (UNITO), New York Presbyterian Hospital, MedImmune

المصدر: ISSN: 0887-6924.

مصطلحات موضوعية: [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology

الوصف: International audience ; This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/ refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

العلاقة: hal-02194148; https://normandie-univ.hal.science/hal-02194148Test; https://normandie-univ.hal.science/hal-02194148/documentTest; https://normandie-univ.hal.science/hal-02194148/file/s41375-018-0210-1.pdfTest

الإتاحة: https://doi.org/10.1038/s41375-018-0210-1Test
https://normandie-univ.hal.science/hal-02194148Test
https://normandie-univ.hal.science/hal-02194148/documentTest
https://normandie-univ.hal.science/hal-02194148/file/s41375-018-0210-1.pdfTest

المؤلفون: Naidus, Elliot, Bouquet, Jerome, Oh, David Y., Looney, Timothy J., Yang, Hai, Fong, Lawrence, Standifer, Nathan E., Zhang, Li

المصدر: Cancer Immunology, Immunotherapy; Jul2021, Vol. 70 Issue 7, p2095-2102, 8p

مصطلحات موضوعية: T cells, TREATMENT effectiveness, PROGRAMMED death-ligand 1, NON-small-cell lung carcinoma, OVERALL survival

مستخلص: Immune checkpoint inhibitors (ICI) are designed to activate exhausted tumor-reactive T cells thereby leading to tumor regression. Durvalumab, an ICI that binds to the programmed death ligand-1 (PD-L1) molecule, is approved as a consolidation therapy for treatment of patients with stage III, unresectable, non-small cell lung cancer (NSCLC). Immunophenotypic analysis of circulating immune cells revealed increases in circulating proliferating CD4 + and CD8 + T cells earlier after durvalumab treatment. To examine durvalumab's mechanism of action and identify potential predictive biomarkers, we assessed the circulating T cells phenotypes and TCR genes of 71 NSCLC patients receiving durvalumab enrolled in a Phase I trial (NCT01693562, September 14, 2012). Next-generation sequencing of TCR repertoire was performed on these NSCLC patients' peripheral blood samples at baseline and day 15. Though patients' TCR repertoire diversity showed mixed responses to the treatment, patients exhibiting increased diversity on day 15 attained significantly longer overall survival (OS) (median OS was not reached vs 17.2 months for those with decreased diversity, p = 0.015). We applied network analysis to assess convergent T cell clonotypes indicative of an antigen-driven immune response. Patients with larger TCR clusters had improved OS (median OS was not reached vs 13.1 months for patients with smaller TCR clusters, p = 0.013). Early TCR repertoire diversification after durvalumab therapy for NSCLC may be predictive of increased survival and provides a mechanistic basis for durvalumab pharmacodynamic activity. [ABSTRACT FROM AUTHOR]

: Copyright of Cancer Immunology, Immunotherapy is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)