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Your search keyword '"Michele Wl, Teng"' showing total 4 results
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4 results on '"Michele Wl, Teng"'

1. Concomitant or delayed anti-TNF differentially impact on immune-related adverse events and antitumor efficacy after anti-CD40 therapy

Author

Jing Liu, Elizabeth McDonald, Mark J Smyth, Celia Jacoberger-Foissac, Stephen J Blake, Hannah Triscott, Kyohei Nakamura, and Michele WL Teng

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Concomitant tumor necrosis factor (TNF) neutralization in combination with immune checkpoint inhibitors (ICIs) reduces clinical immune-related adverse events (irAEs) and appears to improve antitumor efficacy in preclinical tumor models. Agonistic antibodies targeting costimulatory receptors such as CD40 represent an additional strategy to boost antitumor immune response and potentiate the activity of ICIs. However, the dose-limiting toxicities observed in anti-CD40-treated cancer patients have hindered its clinical development.Methods We previously described a mouse model to assess both antitumor activity and irAEs induced by various effective combination immunotherapies. Using the BALB/c and C57BL/6 strains of FoxP3-GFP-DTR (FoxP3DTR) mice, transient depletion of T regulatory cells (Tregs) prior to immunotherapy with additional immunomodulatory antibodies, lowered immune self-tolerance, resulting in the development of a spectrum of physical and biochemical irAEs similar to that reported clinically. In MC38 and 4T1.2 tumor models, following transient Treg depletion, we evaluated the impact of anti-CD40 on antitumor efficacy and the development of irAEs and the impact of concomitant or delayed TNF blockade on both these parameters. Physical irAEs were scored and biochemical irAEs were measured in the serum (ALT and cytokine levels). Histopathological liver and colon tissue analysis were performed to assess immune cell infiltration and tissue damage.Results Similar to early clinical trials of CD40 agonists, in our tumor models we observed liver toxicities and rapid release of proinflammatory cytokines (TNF, interleukin 6, interferon-γ). In the BALB/c strain, anti-CD40 induced severe physical and biochemical irAEs. Concomitant anti-TNF treatment abrogated weight loss, liver damage and colitis, which consequently resulted in an improved clinical score. However, concomitant anti-TNF impaired antitumor response in a proportion of anti-CD40-treated C57BL/6 FoxP3DTR mice. Delaying TNF blockade in these mice reduced biochemical but not physical irAEs while preserving antitumor efficacy.Conclusions Our results suggest concomitant rather than delayed anti-TNF is most effective in reducing biochemical and physical irAEs induced by anti-CD40, although it had the potential to negatively impact antitumor efficacy. Furthermore, our findings highlight the utility of our mouse model to assess the severity of irAEs induced by novel immunotherapeutic agents and evaluate whether their toxicity and antitumor efficacy can be uncoupled.

Published
2020
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2. A Prospective Study Investigating the Efficacy and Toxicity of Definitive ChemoRadadiation and ImmunOtherapy (CRIO) in Locally and/or Regionally Advanced Cutaneous Squamous Cell Carcinoma

Author

Charles Lin, Trishna Ballah, Michelle Nottage, Karen Hay, Benjamin Chua, Lizbeth Kenny, Paul Thomas, Michele WL Teng, Jacqui Keller, Trang Le, Jennifer Edmunds, and Brett GM Hughes

Abstract

Background: Patients with unresectable advanced cutaneous squamous cell carcinoma (cSCC) are generally treated with palliative intent. Immune checkpoint blockade has significant activity in the palliative setting in patients with recurrent or metastatic cSCC. This single arm phase 2 prospective study aims to investigate the combination of curative intent chemoradiation and durvalumab (anti-PD-L1 checkpoint inhibitor) for this patient cohort. Our hypothesis is that >70% of patients with locally-advanced primary disease or regional metastases can be safely treated for cure using ChemoRadiation and ImmunOtherapy (CRIO) compared to the null hypothesis of ≤50%. Methods: Patients with unresectable locally and or regionally advanced pathologically confirmed cSCC deemed suitable for CRIO by consensus of the Head and Neck Multidisciplinary meeting will be eligible. We aim to accrue a total of 15 patients. The co-primary endpoints of CRIO will be the safety of treatment and the complete response rate. Secondary endpoints will include overall survival, progression free survival, and locoregional control. Translational research endpoints including biomarkers will also be explored utilising multiplex immunohistochemistry on tumour biopsy samples obtained prior to commencing treatment and during treatment (week 2). In addition, the utility of CXCR-4 PET scan will be explored.Discussion: CRIO is a novel trial evaluating the combination of curative intent chemoradiotherapy with concurrent durvalumab for patients with inoperable locally advanced cSCC.Trial registration Trial registered with the Australian New Zealand Clinical Trial Registry (ACTRN12618001573246)

Published
2020
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3. Systemic administration of IL-33 induces a population of circulating KLRG1

Author

Camille, Guillerey, Kimberley, Stannard, Jason, Chen, Sophie, Krumeich, Kim, Miles, Kyohei, Nakamura, Jessica, Smith, Yuan, Yu, Susanna, Ng, Heidi, Harjunpää, Michele Wl, Teng, Christian, Engwerda, Gabrielle T, Belz, and Mark J, Smyth

Subjects
Mice, Animals, Cytokines, Humans, Lectins, C-Type, Lymphocytes, Receptors, Immunologic, Interleukin-33, Multiple Myeloma, Immunity, Innate
Abstract

Type 2 innate lymphoid cells (ILC2s) are important producers of type 2 cytokines whose role in hematological cancers remains unclear. ILC2s are a heterogeneous population encompassing distinct subsets with different tissue localization and cytokine responsiveness. In this study, we investigated the role of bone marrow (BM) ILC2s and interleukin (IL)-33-stimulated ILC2s in multiple myeloma, a plasma cell malignancy that develops in the BM. We found that myeloma growth was associated with phenotypic and functional alterations of BM ILC2s, characterized by an increased expression of maturation markers and reduced cytokine response to IL-2/IL-33. We identified a population of KLRG1

Published
2020

4. Anticancer immunotherapy by CTLA-4 blockade: Obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25

Author

Dalil, Hannani, Marie, Vétizou, David, Enot, Sylvie, Rusakiewicz, Nathalie, Chaput, David, Klatzmann, Melanie, Desbois, Nicolas, Jacquelot, Nadège, Vimond, Salem, Chouaib, Christine, Mateus, James P, Allison, Antoni, Ribas, Jedd D, Wolchok, Jianda, Yuan, Philip, Wong, Michael, Postow, Andrzej, Mackiewicz, Jacek, Mackiewicz, Dirk, Schadendorff, Dirk, Jaeger, Inka, Zörnig, Jessica, Hassel, Alan J, Korman, Keith, Bahjat, Michele, Maio, Luana, Calabro, Michele Wl, Teng, Mark J, Smyth, Alexander, Eggermont, Caroline, Robert, Guido, Kroemer, Laurence, Zitvogel, Immunologie des tumeurs et immunothérapie (UMR 1015), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Laboratoire d’Immunomonitoring en Oncologie (LIO), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie - Immunopathologie - Immunothérapie (I3), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Service de dermatologie, Département de médecine oncologique [Gustave Roussy], Memorial Sloane Kettering Cancer Center [New York], Comprehensive Cancer Center, Department of Urology Université de Montréal, Weill Medical College of Cornell University [New York], Department of Diagnostics and Cancer Immunology [Poznan, Poland], Greater Poland Cancer Centre [Poznan, Poland]-Poznan Medical University [Poland], Chair Forest Operat, University of Freiburg [Freiburg], Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Medical Oncology and Immunotherapy, Istituto Toscano Tumori-University Hospital of Siena, Apoptose, cancer et immunité (U848), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11)

Subjects
CD4-Positive T-Lymphocytes, Male, T-Lymphocytes, Medizin, Inbred C57BL, T-Lymphocytes, Regulatory, tumor immunotherapy, Cohort Studies, Mice, Receptors, Monoclonal, 80 and over, CTLA-4 Antigen, ipilimumab, Melanoma, Aged, 80 and over, Antibodies, Monoclonal, Middle Aged, Regulatory, Corrigenda, Recombinant Proteins, 3. Good health, Up-Regulation, 5.1 Pharmaceuticals, cancer, CD122, CTLA-4 blockade, IL-2, sCD25, Female, Original Article, Immunotherapy, Development of treatments and therapeutic interventions, Adult, Adolescent, Clinical Sciences, chemical and pharmacologic phenomena, Antibodies, Young Adult, Animals, Humans, Molecular Biology, Aged, Animal, Interleukin-2 Receptor alpha Subunit, Receptors, Interleukin-2, Cell Biology, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Mice, Inbred C57BL, Disease Models, Animal, Disease Models, Interleukin-2, Biochemistry and Cell Biology, Developmental Biology
Abstract

The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.

Published
2015
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