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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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6. Recruiting the Immune System Against Disease: Lessons for Clinical and Systems Pharmacology

Author

Nathan Standifer, Timothy P. Hickling, and Paolo Vicini

Subjects
Clinical Trials as Topic, business.industry, Systems biology, Systems Biology, Vaccination, lcsh:RM1-950, MEDLINE, Disease, Bioinformatics, Immune system, lcsh:Therapeutics. Pharmacology, Modeling and Simulation, Immune System, Perspective, Pharmacology, Clinical, Medicine, Humans, Pharmacology (medical), Immunotherapy, business, Systems pharmacology, Perspectives
Published
2019

7. Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia

Author

Philippe Rousselot, Shira Dinner, Robert J. Kreitman, Bjørn Tore Gjertsen, Monica Bocchia, Andrzej Hellmann, Lionel Karlin, Fritz Offner, Philipp le Coutre, Gary J. Schiller, Agostino Cortelezzi, Xavier Troussard, Nai Shun Yao, Mirjana Gotic, Shannon Marshall, Tamar Tadmor, Michael Doubek, Ira Pastan, Wyndham H. Wilson, Kemal Balic, Gail J. Roboz, Sascha Dietrich, Peng He, Marco Gobbi, Ronan T. Swords, Francis J. Giles, Loree Larratt, Tadeusz Robak, Dimitri Breems, Tanya Siddiqi, Nathan Standifer, Giuseppe Saglio, Larry Bacon, Douglas E. Gladstone, Krimo Bouabdallah, Pier Luigi Zinzani, Farhad Ravandi, Julio Delgado, Mathias J. Rummel, Cecilia Arana Yi, Frédéric Maloisel, Claire Dearden, Stéphane Leprêtre, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Royal Marsden NHS Foundation Trust, University of Bologna, 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], Clinical Center of Serbia (KCS), University of Alberta, Universiteit Gent = Ghent University [Belgium] (UGENT), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, 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 [Bordeaux], Ziekenhuis Netwerk Antwerpen (ZNA), Università degli Studi di Milano [Milano] (UNIMI), Northwestern University Feinberg School of Medicine, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Justus-Liebig-Universität Gießen (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], University of Turin, New York Presbyterian Hospital, MedImmune, University of Bologna/Università di Bologna, Universiteit Gent = Ghent University (UGENT), University of California (UC)-University of California (UC), Università degli Studi di Milano = University of Milan (UNIMI), 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), Università degli studi di Torino = University of Turin (UNITO), Normandie, Université, Kreitman, Robert J, Dearden, Claire, Zinzani, Pier Luigi, Delgado, Julio, Karlin, Lionel, Robak, Tadeusz, Gladstone, Douglas E, le Coutre, Philipp, Dietrich, Sascha, Gotic, Mirjana, Larratt, Loree, Offner, Fritz, Schiller, Gary, Swords, Ronan, Bacon, Larry, Bocchia, Monica, Bouabdallah, Krimo, Breems, Dimitri A, Cortelezzi, Agostino, Dinner, Shira, Doubek, Michael, Gjertsen, Bjorn Tore, Gobbi, Marco, Hellmann, Andrzej, Lepretre, Stephane, Maloisel, Frederic, Ravandi, Farhad, Rousselot, Philippe, Rummel, Mathia, Siddiqi, Tanya, Tadmor, Tamar, Troussard, Xavier, Yi, Cecilia Arana, Saglio, Giuseppe, Roboz, Gail J, Balic, Kemal, Standifer, Nathan, He, Peng, Marshall, Shannon, Wilson, Wyndham, Pastan, Ira, Yao, Nai-Shun, and Giles, Francis

Subjects
0301 basic medicine, Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Cancer Research, ERADICATION, Peripheral edema, Salvage therapy, Gastroenterology, Moxetumomab pasudotox, 0302 clinical medicine, Medicine and Health Sciences, Medicine, Aged, 80 and over, Leukemia, Hairy Cell, Remission Induction, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Middle Aged, Prognosis, 3. Good health, Survival Rate, Tolerability, Oncology, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, Moxetumomab pasudotox hairy cell leukemia, medicine.symptom, Adult, medicine.medical_specialty, Bacterial Toxins, Exotoxins, MINIMAL RESIDUAL DISEASE, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, DIAGNOSIS, Article, 03 medical and health sciences, Refractory, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Humans, Hairy cell leukemia, RITUXIMAB, IMMUNOHISTOCHEMISTRY, Survival rate, TERM-FOLLOW-UP, Aged, Salvage Therapy, CLADRIBINE, business.industry, medicine.disease, EFFICACY, Minimal residual disease, 030104 developmental biology, ANTIBODY, Drug Resistance, Neoplasm, PATTERNS, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Neoplasm Recurrence, Local, business, Follow-Up Studies
Abstract

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.

Published
2018

8. Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development

Author

Martin Schwickart, Meina Liang, Lorin Roskos, Nathan Standifer, Christopher J. Del Nagro, Inna Vainshtein, and Amy Schneider

Subjects
0301 basic medicine, Histology, Reviews, Computational biology, Review, Biology, Pharmacology, biopharmaceutical, Pathology and Forensic Medicine, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Drug Discovery, medicine, Humans, receptor occupancy, Pharmacokinetics, PKPD relationship, dose selection, medicine.diagnostic_test, flow cytometry, pharmacodynamic biomarker, animal and human studies, clinical trial, Cell Biology, drug development, 030104 developmental biology, Biopharmaceutical, Drug development, 030220 oncology & carcinogenesis, Pharmacodynamics, Biomarker (medicine), target binding, Target binding, Biomarkers, Dose selection
Abstract

Receptor occupancy (RO) assays are designed to quantify the binding of therapeutics to their targets on the cell surface and are frequently used to generate pharmacodynamic (PD) biomarker data in nonclinical and clinical studies of biopharmaceuticals. When combined with the pharmacokinetic (PK) profile, RO data can establish PKPD relationships, which are crucial for informing dose decisions. RO is commonly measured by flow cytometry on fresh blood specimens and is subject to numerous technical and logistical challenges. To ensure that reliable and high quality results are generated from RO assays, careful assay design, key reagent characterization, data normalization/reporting, and thorough planning for implementation are of critical importance during development. In this article, the authors share their experiences and perspectives in these areas and discuss challenges and potential solutions when developing and implementing a flow cytometry‐based RO method in support of biopharmaceutical drug development. © 2015 The Authors Cytometry Part B: Clinical Cytometry Published by Wiley Periodicals, Inc.

Published
2015

9. Discovery of T cell antigens by high-throughput screening of synthetic minigene libraries

Author

Arnold Kas, Srinath Sanda, Brad Stone, Jay Shendure, Katharine Schwedhelm, Martin W. McIntosh, Nirasha Ramchurren, Leonard A. D'Amico, Michael Tasch, Brian D. Hondowicz, Crystal Rawlings, and Nathan Standifer

Subjects
Enzyme-Linked Immunospot Assay, Anatomy and Physiology, T-Lymphocytes, lcsh:Medicine, CD8-Positive T-Lymphocytes, Epitope, Epitopes, 0302 clinical medicine, HLA Antigens, Immune Physiology, Cytotoxic T cell, lcsh:Science, 0303 health sciences, Multidisciplinary, ELISPOT, Epithelial Cell Adhesion Molecule, 3. Good health, Neoplasm Proteins, medicine.anatomical_structure, Medicine, Protein Binding, Research Article, T cell, Immune Cells, Molecular Sequence Data, Immunology, Nerve Tissue Proteins, Computational biology, Human leukocyte antigen, Biology, 03 medical and health sciences, Antigen, Antigens, Neoplasm, medicine, Humans, Amino Acid Sequence, Antigens, Antigen-presenting cell, 030304 developmental biology, Gene Library, lcsh:R, Membrane Proteins, Virology, High-Throughput Screening Assays, Diabetes Mellitus, Type 1, Case-Control Studies, Immunologic Techniques, Clinical Immunology, lcsh:Q, Cell Adhesion Molecules, 030215 immunology, Minigene
Abstract

The identification of novel T cell antigens is central to basic and translational research in autoimmunity, tumor immunology, transplant immunology, and vaccine design for infectious disease. However, current methods for T cell antigen discovery are low throughput, and fail to explore a wide range of potential antigen-receptor interactions. To overcome these limitations, we developed a method in which programmable microarrays are used to cost-effectively synthesize complex libraries of thousands of minigenes that collectively encode the content of hundreds of candidate protein targets. Minigene-derived mRNA are transfected into autologous antigen presenting cells and used to challenge complex populations of purified peripheral blood CD8+ T cells in multiplex, parallel ELISPOT assays. In this proof-of-concept study, we apply synthetic minigene screening to identify two novel pancreatic islet autoantigens targeted in a patient with Type I Diabetes. To our knowledge, this is the first successful screen of a highly complex, synthetic minigene library for identification of a T cell antigen. In principle, responses against the full protein complement of any tissue or pathogen can be assayed by this approach, suggesting that further optimization of synthetic libraries holds promise for high throughput antigen discovery.

Published
2012

10. Changes in autoreactive T cell avidity during type 1 diabetes development

Author

Vivian H. Gersuk, Nathan Standifer, Gerald T. Nepom, Emily Burwell, and Carla J. Greenbaum

Subjects
Adult, CD4-Positive T-Lymphocytes, Male, Adolescent, T cell, Receptors, Antigen, T-Cell, alpha-beta, Immunology, Receptors, Antigen, T-Cell, chemical and pharmacologic phenomena, Autoimmunity, Hemagglutinin Glycoproteins, Influenza Virus, Biology, medicine.disease_cause, Major histocompatibility complex, Lymphocyte Activation, Article, Interferon-gamma, Young Adult, Antigen, Interleukin-15 Receptor alpha Subunit, Antigens, CD, medicine, Immunology and Allergy, Cytotoxic T cell, Humans, Insulin, Avidity, Receptor-Like Protein Tyrosine Phosphatases, Class 8, Glutamate Decarboxylase, T-cell receptor, T lymphocyte, Middle Aged, medicine.anatomical_structure, Diabetes Mellitus, Type 1, biology.protein, Female
Abstract

The activation threshold for antigen-specific T cell responses is dependent on the avidity of the trimolecular interaction between TCR, antigen, and MHC. We compared CD4+ T cell avidities for the diabetes-associated autoantigen glutamic acid decarboxylase 555-567 (GAD 555) among serial samples from autoantibody-positive subjects at high risk of progression to type 1 diabetes (T1D). T cells from three at-risk subjects demonstrated significant avidity increases (p

Published
2009

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