31 results on '"Alves Costa Silva C"'
Search Results
2. 259MO A predictive score of cancer immunotherapy responses based on ecological analysis of gut microbiota
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Derosa, L., primary, Alves Costa Silva, C., additional, Iebba, V., additional, Routy, B., additional, Reni, A., additional, Audigier-Valette, C., additional, Zalcman, G., additional, Mazieres, J., additional, Friard, S., additional, Goldwasser, F., additional, Moro-Sibilot, D., additional, Scherpereel, A., additional, Pegliasco, H., additional, Martinez, S., additional, Escudier, B., additional, Planchard, D., additional, Albiges, L., additional, Besse, B., additional, Barlesi, F., additional, and Zitvogel, L., additional
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- 2022
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3. 1480P Baseline levels of proinflammatory cytokines according to body mass index (BMI) and BMI impact on clinical outcomes in metastatic renal cell carcinoma (mRCC) patients (pts) treated with nivolumab (NIVO) within the NIVOREN trial
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Colomba, E., primary, Carril Ajuria, L., additional, Dalban, C., additional, Derosa, L., additional, Alves Costa Silva, C., additional, Rassy, E., additional, Negrier, S., additional, Chevreau, C.M., additional, Gravis Mescam, G., additional, Oudard, S., additional, Laguerre, B., additional, Barthelemy, P., additional, Gross Goupil, M., additional, Geoffrois, L., additional, Thiery-Vuillemin, A., additional, Joly Lobbedez, F., additional, Ladoire, S., additional, Tantot, F., additional, Escudier, B., additional, and Albiges, L., additional
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- 2022
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4. 1172O Akkermansia muciniphila-based multi-omic profiling in advanced non-small cell lung cancer
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Belluomini, L., Bonato, A., Almonte, A., Gattazzo, F., Lebhar, I., Birebent, R., Flament, C., Xiberras, M., Marques, M., Ly, P., Thelemaque, C., Parisi, C., Remon Masip, J., Besse, B., Planchard, D., Alves Costa Silva, C., Barlesi, F., Zitvogel, L., and Derosa, L.
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- 2024
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5. 697P Impact of β-blockers (BB) on outcomes of metastatic renal cell carcinoma (mRCC) patients treated with nivolumab (N)
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Alves Costa Silva, C., primary, Derosa, L., additional, Dalban, C., additional, Colomba, E., additional, Negrier, S., additional, Chevreau, C.M., additional, Gravis, G., additional, Oudard, S.M., additional, Laguerre, B., additional, Barthelemy, P., additional, Borchiellini, D., additional, Gross-Goupil, M., additional, Geoffrois, L., additional, Rolland, F., additional, Thiery-Vuillemin, A., additional, Joly, F., additional, Ladoire, S., additional, Tantot, F., additional, Escudier, B., additional, and Albiges, L., additional
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- 2021
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6. 657MO Antibiotic (ATB) therapy and outcome from nivolumab (N) in metastatic renal cell carcinoma (mRCC) patients (pts): Results of the GETUG-AFU 26 NIVOREN multicentric phase II study
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Derosa, L., primary, Alves Costa Silva, C., additional, Dalban, C., additional, Colomba, E., additional, Negrier, S., additional, Chevreau, C.M., additional, Gravis, G., additional, Oudard, S.M., additional, Laguerre, B., additional, Barthelemy, P., additional, Borchiellini, D., additional, Gross-Goupil, M., additional, Geoffrois, L., additional, Rolland, F., additional, Thiery-Vuillemin, A., additional, Joly, F., additional, Ladoire, S., additional, Tantot, F., additional, Escudier, B., additional, and Albiges, L., additional
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- 2021
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7. 743P Activity of systemic therapies after cabozantinib (CABO) in patients (pts) with metastatic renal cell carcinoma (mRCC)
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Cerbone, L., primary, Di Nunno, V., additional, Carril, L., additional, Benchimol-Zouari, A., additional, Flippot, R., additional, Alves Costa Silva, C., additional, Colomba-Blameble, E., additional, Guida, A., additional, Derosa, L., additional, Escudier, B., additional, and Albiges, L., additional
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- 2020
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8. 1452MO Longitudinal analysis reveals gut microbiota shift during standard therapies in metastatic renal cell carcinoma (mRCC)
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Alves Costa Silva, C., Piccinno, G., Cerbone, L., Iebba, V., Colomba, E., Flippot, R., C. Sow, Darik, I., Maltez Thomas, A., Naoun, N., Bernard-Tessier, A., Reni, A., Segata, N., Escudier, B., Zitvogel, L., Albiges, L., and Derosa, L.
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- 2022
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9. Skeletal muscle loss as an adverse event during cabozantinib treatment in patients with metastatic renal cell carcinoma
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Alves Costa Silva, C., primary, Afonso, D., additional, Colomba, E., additional, Le Teuff, G., additional, Derosa, L., additional, Raynard, B., additional, Guida, A., additional, Benchimol-Zouari, A., additional, Escudier, B., additional, Bidault, F., additional, and Albiges, L., additional
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- 2019
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10. Weight loss is an underestimated adverse event with cabozantinib in patients with metastastic renal cell carcinoma (mRCC)
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Colomba, E., primary, Alves Costa Silva, C., additional, Le Teuff, G., additional, Benchimol-Zouari, A., additional, Guida, A., additional, Derosa, L., additional, Raynard, B., additional, Escudier, B., additional, and Albiges, L., additional
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- 2019
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11. 974P - Prior tyrosine kinase inhibitors (TKI) and antibiotics (ATB) use are associated with distinct gut microbiota ‘guilds’ in renal cell carcinoma (RCC) patients
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Iebba, V., Albiges, L., Alla, L., Colomba, E., Alves Costa Silva, C., Pons, N., Baciarello, G., Le Chatelier, E., Fizazi, K., Routy, B., Escudier, B., Zitvogel, L., and Derosa, L.
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- 2019
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12. 965P - Weight loss is an underestimated adverse event with cabozantinib in patients with metastastic renal cell carcinoma (mRCC)
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Colomba, E., Alves Costa Silva, C., Le Teuff, G., Benchimol-Zouari, A., Guida, A., Derosa, L., Raynard, B., Escudier, B., and Albiges, L.
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- 2019
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13. 967P - Skeletal muscle loss as an adverse event during cabozantinib treatment in patients with metastatic renal cell carcinoma
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Alves Costa Silva, C., Afonso, D., Colomba, E., Le Teuff, G., Derosa, L., Raynard, B., Guida, A., Benchimol-Zouari, A., Escudier, B., Bidault, F., and Albiges, L.
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- 2019
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14. Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients
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Conrad Rauber, Gladys Ferrere, Jean-Eudes Fahrner, Valerio Iebba, Nicolas Pons, Romain Daillère, Emmanuelle Le Chatellier, Hugo Roume, Filippo Pietrantonio, Nicola Segata, Marine Fidelle, Anne-Gaëlle Goubet, Carolina Alves Costa Silva, Bertrand Routy, Connie P.M. Duong, Karim Fizazi, Edoardo Pasolli, Safae Terrisse, Beatrice Casu, Laurence Albiges, Bernard Escudier, Mélodie Bonvalet, Maryam Tidjani Alou, Laurie Alla, Kristina Iribarren, Didier Raoult, Aude Desnoyer, Guido Kroemer, Lisa Derosa, Laura Mondragón, Nathalie Galleron, Anna Reni, Fabien Lemaitre, Laurence Zitvogel, Derosa, L., Routy, B., Fidelle, M., Iebba, V., Alla, L., Pasolli, E., Segata, N., Desnoyer, A., Pietrantonio, F., Ferrere, G., Fahrner, J. -E., Le Chatellier, E., Pons, N., Galleron, N., Roume, H., Duong, C. P. M., Mondragon, L., Iribarren, K., Bonvalet, M., Terrisse, S., Rauber, C., Goubet, A. -G., Daillere, R., Lemaitre, F., Reni, A., Casu, B., Alou, M. T., Alves Costa Silva, C., Raoult, D., Fizazi, K., Escudier, B., Kroemer, G., Albiges, L., Zitvogel, L., Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Faculté de médecine de l'Université Paris-Sud [Kremlin Bicêtre, Paris], Université Paris-Saclay, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), MetaGenoPolis (MGP (US 1367)), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Naples Federico II = Università degli studi di Napoli Federico II, Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], 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), Institut Gustave Roussy (IGR), IRCCS Istituto Nazionale dei Tumori [Milano], Université Paris-Sud - Paris 11 (UP11), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Suzhou Institute of Systems Medicine [Jiangsu, P.R. China], Karolinska University Hospital [Stockholm], Philanthropia Foundation ESMO translational research fellowship Fonds de la Recherche en Sante du Quebec Kidney Cancer Research Network of Canada Ligue nationale contre le cancerFrench National Research Agency (ANR)French National Research Agency (ANR)ERA-Net for Research on Rare Diseases Fondation ARC pour la Recherche sur le CancerRegion Ile-de-France Fondation de FranceFondation pour la Recherche MedicaleEuropean Commission Joint Research CentreEuropean Research Council (ERC)Fondation Carrefour, High-end Foreign Expert Program in China GDW20171100085 GDW20181100051Institut National du Cancer (INCA) FranceInserm (HTE) Institut Universitaire de France Leducq FoundationSearave and Carrefour Foundation SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE 2.0) BMS Foundation SIRIC Cancer Research and Personalized Medicine (CARPEM) Paris Alliance of Cancer Research Institutes (PACRI) Mediterranee Infection 10-IAHU-03Region Provence-Alpes-Cote d'AzurNational Research, Development and Innovation Fund of Hungary FIEK_16-1-20160005Research and Technology Innovation Fund NAP2-2017-1.2.1-NKP-0002Breast Cancer Research Foundation BCRF-17-156Novo Nordisk Foundation Interdisciplinary Synergy Program Grant NNF15OC0016584, ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), European Project: 825410,ONCOBIOME, University of Naples Federico II, 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), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Gustave Roussy Cancer Campus (GRCC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Saclay, Université Paris-Sud [Le Kremlin-Bicêtre] (Faculté de Médecine), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CRCHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Centre d’Investigation Clinique en Biothérapies [CHU Pitié-Salpêtrière] (CIC-BT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université Paris-Saclay, Faculté de Pharmacie, 92290 Châtenay-Malabry, France, MetaGenoPolis, European Institute of Oncology [Milan] (ESMO), Gustave Roussy Cancer Campus, Partenaires INRAE, Chinese Academy of Medical Sciences, Philanthropia Foundation ESMO translational research fellowship.Fonds de la Recherche en Sante du Quebec Kidney Cancer Research Network of CanadaLigue nationale contre le cancerFrench National Research Agency (ANR) ERA-Net for Research on Rare DiseasesFondation ARC pour la Recherche sur le CancerRegion Ile-de-FranceFondation de FranceFondation pour la Recherche MedicaleEuropean Commission Joint ResearchCentre European Research Council (ERC)Fondation Carrefour, and High-end Foreign Expert Program in China GDW20171100085 GDW20181100051Institut National du Cancer (INCA) France Inserm (HTE) Institut Universitaire de FranceLeducq FoundationSearave and Carrefour Foundation SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE 2.0) BMS Foundation SIRIC Cancer Research and Personalized Medicine (CARPEM) Paris Alliance of Cancer Research Institutes (PACRI)Mediterranee Infection 10-IAHU-03Region Provence-Alpes-Cote d'AzurNational Research, Development and Innovation Fund of Hungary FIEK_16-1-20160005Research and Technology Innovation Fund NAP2-2017-1.2.1-NKP-0002Breast Cancer Research Foundation BCRF-17-156Novo Nordisk Foundation Interdisciplinary Synergy Program Grant NNF15OC0016584
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Oncology ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Antibiotics ,030232 urology & nephrology ,Tyrosine kinase inhibitor ,Immune checkpoint inhibitor ,Tyrosine-kinase inhibitor ,Feces ,Mice ,0302 clinical medicine ,Cancer immunotherapy ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Renal cell carcinoma ,Prospective Studies ,Immune Checkpoint Inhibitors ,[SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases ,Microbiota ,Kidney cancer ,Kidney Neoplasms ,3. Good health ,Nivolumab ,030220 oncology & carcinogenesis ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,medicine.medical_specialty ,medicine.drug_class ,Urology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Predictive Value of Tests ,Internal medicine ,medicine ,Animals ,Humans ,[SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology ,Carcinoma, Renal Cell ,[SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health ,business.industry ,Antibiotic ,Immunotherapy ,medicine.disease ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,Immune checkpoint ,Gastrointestinal Microbiome ,Drug Resistance, Neoplasm ,business - Abstract
Background: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC. Objective: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients. Design, setting, and participants: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed. Outcome measurements and statistical analysis: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients’ therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors. Results and limitations: Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae). Conclusions: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers. Patient summary: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy. Antibiotics prior to immune checkpoint inhibitors have a deleterious clinical impact, reduce the microbiome diversity, and increase Clostridium hathewayi bacteria associated with resistance. Higher baseline microbiome diversity and Akkermansia muciniphila are associated with longer progression-free survival. In murine fecal microbiome transplantation experiments, A. muciniphila can restore the anticancer activity of the combination of anti–PD-1 and CTLA-4.
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- 2020
15. State of the art and the future of microbiome-based biomarkers: a multidisciplinary Delphi consensus.
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Rodriguez J, Hassani Z, Alves Costa Silva C, Betsou F, Carraturo F, Fasano A, Israelsen M, Iyappan A, Krag A, Metwaly A, Schierwagen R, Trebicka J, Zwart H, Doré J, Cordaillat-Simmons M, and Druart C
- Abstract
Although microbiome signatures have been identified in various contexts (ie, pathogenesis of non-communicable diseases and treatment response), qualified microbiome-based biomarkers are currently not in use in clinical practice. The Human Microbiome Action consortium initiated a Delphi survey to establish a consensus on the needs, challenges, and limitations in developing qualified microbiome-based biomarkers. The questionnaire was developed by a scientific committee via literature review and expert interviews. To ensure broad applicability of the results, 307 experts were invited to participate; 114 of them responded to the first round of the survey, 93 of whom completed the second and final round as well. The survey highlighted the experts' confidence in the potential of microbiome-based biomarkers for several indications or pathologies. The paucity of validated analytical methods appears to be the principal factor hindering the qualification of these biomarkers. The survey also showed that clinical implementation of these biomarkers would only be possible if kitted and validated molecular assays with simple interpretation are developed. This initiative serves as a foundation for designing and implementing public-private collaborative projects to overcome the challenges and promote clinical application of microbiome-based biomarkers., Competing Interests: Declaration of interests JD is a cofounder and scientific adviser of GMT Science and MaaT Pharma. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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16. Acyl-CoA binding protein for the experimental treatment of anorexia.
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Chen H, Moriceau S, Joseph A, Mailliet F, Li S, Tolle V, Duriez P, Dardennes R, Durand S, Carbonnier V, Stoll G, Sauvat A, Lachkar S, Aprahamian F, Alves Costa Silva C, Pan H, Montégut L, Anagnostopoulos G, Lambertucci F, Motiño O, Nogueira-Recalde U, Bourgin M, Mao M, Pan Y, Cerone A, Boedec E, Gouveia ZL, Marmorino F, Cremolini C, Derosa L, Zitvogel L, Kepp O, López-Otín C, Maiuri MC, Perez F, Gorwood P, Ramoz N, Oury F, Martins I, and Kroemer G
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- Animals, Humans, Mice, Transgenic, Mice, Anorexia Nervosa metabolism, Anorexia Nervosa drug therapy, Lipocalin-2 metabolism, Lipocalin-2 blood, Hypothalamus metabolism, Male, Female, Mice, Inbred C57BL, Restraint, Physical, Hepatocytes metabolism, Hepatocytes drug effects, Diazepam Binding Inhibitor metabolism, Anorexia drug therapy, Anorexia metabolism
- Abstract
Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.
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- 2024
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17. Influence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial.
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Alves Costa Silva C, Piccinno G, Suissa D, Bourgin M, Schreibelt G, Durand S, Birebent R, Fidelle M, Sow C, Aprahamian F, Manghi P, Punčochář M, Asnicar F, Pinto F, Armanini F, Terrisse S, Routy B, Drubay D, Eggermont AMM, Kroemer G, Segata N, Zitvogel L, Derosa L, Bol KF, and de Vries IJM
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- Humans, Metabolic Reprogramming, Dendritic Cells, Melanoma, Microbiota genetics
- Abstract
Tumor immunosurveillance plays a major role in melanoma, prompting the development of immunotherapy strategies. The gut microbiota composition, influencing peripheral and tumoral immune tonus, earned its credentials among predictors of survival in melanoma. The MIND-DC phase III trial (NCT02993315) randomized (2:1 ratio) 148 patients with stage IIIB/C melanoma to adjuvant treatment with autologous natural dendritic cell (nDC) or placebo (PL). Overall, 144 patients collected serum and stool samples before and after 2 bimonthly injections to perform metabolomics (MB) and metagenomics (MG) as prespecified exploratory analysis. Clinical outcomes are reported separately. Here we show that different microbes were associated with prognosis, with the health-related Faecalibacterium prausnitzii standing out as the main beneficial taxon for no recurrence at 2 years (p = 0.008 at baseline, nDC arm). Therapy coincided with major MB perturbations (acylcarnitines, carboxylic and fatty acids). Despite randomization, nDC arm exhibited MG and MB bias at baseline: relative under-representation of F. prausnitzii, and perturbations of primary biliary acids (BA). F. prausnitzii anticorrelated with BA, medium- and long-chain acylcarnitines. Combined, these MG and MB biomarkers markedly determined prognosis. Altogether, the host-microbial interaction may play a role in localized melanoma. We value systematic MG and MB profiling in randomized trials to avoid baseline differences attributed to host-microbe interactions., (© 2024. The Author(s).)
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- 2024
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18. Gut microbiome predicts gastrointestinal toxicity outcomes from chemoradiation therapy in patients with head and neck squamous cell carcinoma.
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Hes C, Desilets A, Tonneau M, El Ouarzadi O, De Figueiredo Sousa M, Bahig H, Filion É, Nguyen-Tan PF, Christopoulos A, Benlaïfaoui M, Derosa L, Alves Costa Silva C, Ponce M, Malo J, Belkad W, Charpentier D, Aubin F, Hamilou Z, Jamal R, Messaoudene M, Soulières D, and Routy B
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- Male, Humans, Female, Squamous Cell Carcinoma of Head and Neck complications, Prospective Studies, Chemoradiotherapy adverse effects, Head and Neck Neoplasms complications, Mucositis etiology, Gastrointestinal Microbiome
- Abstract
Objectives: Chemoradiation (CRT) in patients with locally advanced head and neck squamous cell cancer (HNSCC) is associated with significant toxicities, including mucositis. The gut microbiome represents an emerging hallmark of cancer and a potentially important biomarker for CRT-related adverse events. This prospective study investigated the association between the gut microbiome composition and CRT-related toxicities in patients with HNSCC, including mucositis., Materials and Methods: Stool samples from patients diagnosed with locally advanced HNSCC were prospectively collected prior to CRT initiation and analyzed using shotgun metagenomic sequencing to evaluate gut microbiome composition at baseline. Concurrently, clinicopathologic data, survival outcomes and the incidence and grading of CRT-emergent adverse events were documented in all patients., Results: A total of 52 patients were included, of whom 47 had baseline stool samples available for metagenomic analysis. Median age was 62, 83 % patients were men and 54 % had stage III-IV disease. All patients developed CRT-induced mucositis, including 42 % with severe events (i.e. CTCAE v5.0 grade ≥ 3) and 25 % who required enteral feeding. With a median follow-up of 26.5 months, patients with severe mucositis had shorter overall survival (HR = 3.3, 95 %CI 1.0-10.6; p = 0.02) and numerically shorter progression-free survival (HR = 2.8, 95 %CI, 0.8-9.6; p = 0.09). The gut microbiome beta-diversity of patients with severe mucositis differed from patients with grades 1-2 mucositis (p = 0.04), with enrichment in Mediterraneibacter (Ruminococcus gnavus) and Clostridiaceae family members, including Hungatella hathewayi. Grade 1-2 mucositis was associated with enrichment in Eubacterium rectale, Alistipes putredinis and Ruminococcaceae family members. Similar bacterial profiles were observed in patients who required enteral feeding., Conclusion: Patients who developed severe mucositis had decreased survival and enrichment in specific bacteria associated with mucosal inflammation. Interestingly, these same bacteria have been linked to immune checkpoint inhibitor resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2024
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19. A microbiota-modulated checkpoint directs immunosuppressive intestinal T cells into cancers.
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Fidelle M, Rauber C, Alves Costa Silva C, Tian AL, Lahmar I, de La Varende AM, Zhao L, Thelemaque C, Lebhar I, Messaoudene M, Pizzato E, Birebent R, Mbogning Fonkou MD, Zoppi S, Reni A, Dalban C, Leduc M, Ferrere G, Durand S, Ly P, Silvin A, Mulder K, Dutertre CA, Ginhoux F, Yonekura S, Roberti MP, Tidjani-Alou M, Terrisse S, Chen J, Kepp O, Schippers A, Wagner N, Suárez-Gosálvez J, Kobold S, Fahrner JE, Richard C, Bosq J, Lordello L, Vitali G, Galleron N, Quinquis B, Le Chatelier E, Blanchard L, Girard JP, Jarry A, Gervois N, Godefroy E, Labarrière N, Koschny R, Daillère R, Besse B, Truntzer C, Ghiringhelli F, Coatnoan N, Mhanna V, Klatzmann D, Drubay D, Albiges L, Thomas AM, Segata N, Danlos FX, Marabelle A, Routy B, Derosa L, Kroemer G, and Zitvogel L
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- Animals, Humans, Mice, Bacteria immunology, Cell Movement, Fecal Microbiota Transplantation, Interleukin-17 metabolism, Th17 Cells immunology, Gastrointestinal Tract immunology, Gastrointestinal Tract microbiology, Anti-Bacterial Agents adverse effects, Cell Adhesion Molecules metabolism, Drug Resistance, Neoplasm, Gastrointestinal Microbiome immunology, Immune Checkpoint Inhibitors therapeutic use, Immune Tolerance drug effects, Immunologic Surveillance, Integrins metabolism, Mucoproteins metabolism, Neoplasms immunology, Neoplasms therapy
- Abstract
Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4β7
+ CD4+ regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4β7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1-α4β7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.- Published
- 2023
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20. Escherichia coli-Specific CXCL13-Producing TFH Are Associated with Clinical Efficacy of Neoadjuvant PD-1 Blockade against Muscle-Invasive Bladder Cancer.
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Goubet AG, Lordello L, Alves Costa Silva C, Peguillet I, Gazzano M, Mbogning-Fonkou MD, Thelemaque C, Lebacle C, Thibault C, Audenet F, Pignot G, Gravis G, Helissey C, Campedel L, Roupret M, Xylinas E, Ouzaid I, Dubuisson A, Mazzenga M, Flament C, Ly P, Marty V, Signolle N, Sauvat A, Sbarrato T, Filahi M, Davin C, Haddad G, Bou Khalil J, Bleriot C, Danlos FX, Dunsmore G, Mulder K, Silvin A, Raoult T, Archambaud B, Belhechmi S, Gomperts Boneca I, Cayet N, Moya-Nilges M, Mallet A, Daillere R, Rouleau E, Radulescu C, Allory Y, Fieschi J, Rouanne M, Ginhoux F, Le Teuff G, Derosa L, Marabelle A, Van Dorp J, Van Dijk N, Van Der Heijden MS, Besse B, Andre F, Merad M, Kroemer G, Scoazec JY, Zitvogel L, and Loriot Y
- Subjects
- B7-H1 Antigen, Chemokine CXCL13, Escherichia coli, Humans, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Immunoglobulin G, Muscles, Neoadjuvant Therapy, Programmed Cell Death 1 Receptor, T-Lymphocytes, Helper-Inducer, Treatment Outcome, Urinary Bladder Neoplasms drug therapy
- Abstract
Biomarkers guiding the neoadjuvant use of immune-checkpoint blockers (ICB) are needed for patients with localized muscle-invasive bladder cancers (MIBC). Profiling tumor and blood samples, we found that follicular helper CD4+ T cells (TFH) are among the best therapeutic targets of pembrolizumab correlating with progression-free survival. TFH were associated with tumoral CD8 and PD-L1 expression at baseline and the induction of tertiary lymphoid structures after pembrolizumab. Blood central memory TFH accumulated in tumors where they produce CXCL13, a chemokine found in the plasma of responders only. IgG4+CD38+ TFH residing in bladder tissues correlated with clinical benefit. Finally, TFH and IgG directed against urothelium-invasive Escherichia coli dictated clinical responses to pembrolizumab in three independent cohorts. The links between tumor infection and success of ICB immunomodulation should be prospectively assessed at a larger scale., Significance: In patients with bladder cancer treated with neoadjuvant pembrolizumab, E. coli-specific CXCL13 producing TFH and IgG constitute biomarkers that predict clinical benefit. Beyond its role as a biomarker, such immune responses against E. coli might be harnessed for future therapeutic strategies. This article is highlighted in the In This Issue feature, p. 2221., (©2022 American Association for Cancer Research.)
- Published
- 2022
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21. Weight and skeletal muscle loss with cabozantinib in metastatic renal cell carcinoma.
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Colomba E, Alves Costa Silva C, Le Teuff G, Elmawieh J, Afonso D, Benchimol-Zouari A, Guida A, Derosa L, Flippot R, Raynard B, Escudier B, Bidault F, and Albiges L
- Subjects
- Anilides, Body Weight, Female, Humans, Male, Middle Aged, Muscle, Skeletal diagnostic imaging, Muscle, Skeletal pathology, Protein Kinase Inhibitors adverse effects, Pyridines, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Carcinoma, Renal Cell secondary, Kidney Neoplasms chemically induced, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology, Sarcopenia pathology
- Abstract
Background: Cabozantinib, a standard of care metastatic renal cell carcinoma (mRCC), may be associated with weight and muscle loss. These effects of new generation VEGFR tyrosine kinase inhibitor on muscle mass loss are poorly described., Methods: All cabozantinib-treated mRCC patients from January 2014 to February 2019 in our institution were included. Clinical data including weight were collected during therapy. Computed tomography images were centrally reviewed for response assessment, and axial sections at the third lumbar vertebrae were used to measure the total muscle area. Toxicities and cabozantinib outcomes were evaluated. Co-primary endpoints included skeletal muscle loss and weight loss (WL), longitudinally evaluated during treatment. WL has been classified according to CTCAEv5.0: Grade 1 (loss of 5 to <10% of baseline body weight), Grade 2 (loss of 10% to <20% of baseline body weight), and Grades 3-4 (loss >20% of baseline body weight)., Results: Patients were mostly men (70.3%), median age was 59.2 (range: 22.0-78.0) years, and median baseline body mass index was 25.0 (range: 16.4-49.3) kg/cm
2 . Prognosis according to International Metastatic RCC Database Consortium score was good, intermediate, and poor for 13 (13.0%), 63 (63.0%), and 24 (24.0%) patients, respectively. Out of a total of 120 patients, 101 patients with a median follow-up of 22.3 months (range: 4.5-62.2) were eligible for analysis; 85 experienced muscle loss and muscle loss >10% increased during cabozantinib exposition, especially after 6 months of treatment. At cabozantinib baseline, 71 patients (70.3%) had sarcopenia, and 16/30 (53.3%) non-sarcopenic patients developed sarcopenia during treatment. Baseline sarcopenia was associated with lower response rates (P = 0.031) and higher grades 3-4 toxicities (P = 0.001). Out of 92 patients included in the WL analysis, 44 (47.8%) and 12 (13.0%) experienced grades 2 and 3 WL, respectively., Conclusions: We report a high incidence of grades 3-4 WL, fourth times higher than reported in prior pivotal trials, and half of the patients developed sarcopenia while on cabozantinib treatment. Weight and muscle mass loss with cabozantinib are underreported and may require further investigations and early management., (© 2022 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.)- Published
- 2022
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22. Efficacy and Safety of Concomitant Proton Pump Inhibitor and Nivolumab in Renal Cell Carcinoma: Results of the GETUG-AFU 26 NIVOREN Multicenter Phase II Study.
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Rassy E, Dalban C, Colomba E, Derosa L, Alves Costa Silva C, Negrier S, Chevreau C, Gravis G, Oudard S, Laguerre B, Barthelemy P, Goupil MG, Geoffrois L, Rolland F, Thiery-Vuillemin A, Joly F, Ladoire S, Tantot F, Escudier B, and Albiges L
- Subjects
- Female, Humans, Immune Checkpoint Inhibitors adverse effects, Male, Nivolumab adverse effects, Proton Pump Inhibitors adverse effects, Retrospective Studies, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology
- Abstract
Introduction: Proton pump inhibitors (PPI) may influence the gut microbiome and thus impact the effectiveness of immune checkpoint inhibitors (ICI). The effect of PPIs on the outcomes of ICI has not been fully explored and investigated in metastatic renal cell carcinoma (mRCC)., Methods: This retrospective analysis used prospectively collected data from the GETUG-AFU 26 NIVOREN (NCT03013335) phase II study which enrolled 729 mRCC patients of whom 720 were treated with nivolumab. The main objective of this analysis was to evaluate the impact of PPI on the efficacy and safety outcomes of mRCC patients. PPI use was defined as PPI administration on the day of ICI initiation., Results: Of the 707 patients with mRCC analyzed in this study, 196 (27.7%) were PPI users. The majority of PPI users were males (80.6%), had an ECOG performance status of 0-1 (78.9%) and a nephrectomy (82.1%). Almost two-thirds of the patients had a favorable and intermediate IMDC risk category and 52% received nivolumab in the third line and beyond. PPI use did not correlate with PFS or OS (HR = 0.89, 95% CI 0.74-1.08 and HR = 1.24; 95% CI, 0.98-1.58, respectively). Grade 3-5 nivolumab-related adverse events were more common among PPI users (25.5% vs. 15.3%)., Conclusions: This real-world study suggests that PPI use in patients with mRCC does not impact the efficacy outcomes but may influence the safety of nivolumab which warrants further investigations., (Copyright © 2022. Published by Elsevier Inc.)
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- 2022
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23. Cancer Induces a Stress Ileopathy Depending on β-Adrenergic Receptors and Promoting Dysbiosis that Contributes to Carcinogenesis.
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Yonekura S, Terrisse S, Alves Costa Silva C, Lafarge A, Iebba V, Ferrere G, Goubet AG, Fahrner JE, Lahmar I, Ueda K, Mansouri G, Pizzato E, Ly P, Mazzenga M, Thelemaque C, Fidelle M, Jaulin F, Cartry J, Deloger M, Aglave M, Droin N, Opolon P, Puget A, Mann F, Neunlist M, Bessard A, Aymeric L, Matysiak-Budnik T, Bosq J, Hofman P, Duong CPM, Ugolini S, Quiniou V, Berrard S, Ryffel B, Kepp O, Kroemer G, Routy B, Lordello L, Bani MA, Segata N, Yengej FY, Clevers H, Scoazec JY, Pasolli E, Derosa L, and Zitvogel L
- Subjects
- Carcinogenesis pathology, Humans, Intestinal Mucosa pathology, Signal Transduction, Dysbiosis chemically induced, Dysbiosis complications, Dysbiosis pathology, Receptors, Adrenergic, beta
- Abstract
Gut dysbiosis has been associated with intestinal and extraintestinal malignancies, but whether and how carcinogenesis drives compositional shifts of the microbiome to its own benefit remains an open conundrum. Here, we show that malignant processes can cause ileal mucosa atrophy, with villous microvascular constriction associated with dominance of sympathetic over cholinergic signaling. The rapid onset of tumorigenesis induced a burst of REG3γ release by ileal cells, and transient epithelial barrier permeability that culminated in overt and long-lasting dysbiosis dominated by Gram-positive Clostridium species. Pharmacologic blockade of β-adrenergic receptors or genetic deficiency in Adrb2 gene, vancomycin, or cohousing of tumor bearers with tumor-free littermates prevented cancer-induced ileopathy, eventually slowing tumor growth kinetics. Patients with cancer harbor distinct hallmarks of this stress ileopathy dominated by Clostridium species. Hence, stress ileopathy is a corollary disease of extraintestinal malignancies requiring specific therapies., Significance: Whether gut dysbiosis promotes tumorigenesis and how it controls tumor progression remain open questions. We show that 50% of transplantable extraintestinal malignancies triggered a β-adrenergic receptor-dependent ileal mucosa atrophy, associated with increased gut permeability, sustained Clostridium spp.-related dysbiosis, and cancer growth. Vancomycin or propranolol prevented cancer-associated stress ileopathy. This article is highlighted in the In This Issue feature, p. 873., (©2021 American Association for Cancer Research.)
- Published
- 2022
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24. The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals.
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Fahrner JE, Lahmar I, Goubet AG, Haddad Y, Carrier A, Mazzenga M, Drubay D, Alves Costa Silva C, de Sousa E, Thelemaque C, Melenotte C, Dubuisson A, Geraud A, Ferrere G, Birebent R, Bigenwald C, Picard M, Cerbone L, Lérias JR, Laparra A, Bernard-Tessier A, Kloeckner B, Gazzano M, Danlos FX, Terrisse S, Pizzato E, Flament C, Ly P, Tartour E, Benhamouda N, Meziani L, Ahmed-Belkacem A, Miyara M, Gorochov G, Barlesi F, Trubert A, Ungar B, Estrada Y, Pradon C, Gallois E, Pommeret F, Colomba E, Lavaud P, Deloger M, Droin N, Deutsch E, Gachot B, Spano JP, Merad M, Scotté F, Marabelle A, Griscelli F, Blay JY, Soria JC, Merad M, André F, Villemonteix J, Chevalier MF, Caillat-Zucman S, Fenollar F, Guttman-Yassky E, Launay O, Kroemer G, La Scola B, Maeurer M, Derosa L, and Zitvogel L
- Subjects
- Antibodies, Neutralizing, Humans, SARS-CoV-2, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics, Antiviral Restriction Factors immunology, COVID-19 immunology, Neoplasms complications, T-Lymphocytes immunology
- Abstract
Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants., Significance: This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike. See related commentary by McGary and Vardhana, p. 892. This article is highlighted in the In This Issue feature, p. 873., (©2022 The Authors; Published by the American Association for Cancer Research.)
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- 2022
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25. Activity of Systemic Treatments After Cabozantinib Failure in Advanced Metastatic Renal Cell Carcinoma.
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Cerbone L, Nunno VD, Carril Ajuria L, Alves Costa Silva C, Colomba E, Guida A, Salviat F, Hirsch L, Benchimol-Zouari A, Flippot R, Escudier B, and Albiges L
- Subjects
- Anilides, Axitinib therapeutic use, Everolimus therapeutic use, Female, Humans, Immune Checkpoint Inhibitors, Male, Protein Kinase Inhibitors, Pyridines, Retrospective Studies, Antineoplastic Agents, Carcinoma, Renal Cell pathology, Kidney Neoplasms pathology
- Abstract
Background: Cabozantinib, a potent multityrosine kinases inhibitor (TKI), has demonstrated overall survival (OS) benefit over everolimus in patients previously treated with VEGFR TKI for metastatic Renal Cell Carcinoma (mRCC). The efficacy of systemic treatments after cabozantinib failure has not been investigated., Materials and Methods: We conducted a retrospective study on patients receiving systemic treatment after cabozantinib failure in heavily pretreated patient with mRCC. We assessed Time to Treatment Failure (TTF), OS and objective response rate (ORR)., Results: Among 150 patients treated with cabozantinib in our institution, 56 (37.3%) received subsequent systemic therapy and were eligible for the analysis. IMDC prognostic group was good, intermediate and poor in 11 (19.6%), 24 (42.9%) and 11 (19.6%) patients, respectively. Cabozantinib was administered mainly as a second (41.1%), or third (33.9%) line treatment. axitinib or immune-checkpoint inhibitors were the subsequent treatment in 18 (34.8%) patients for each everolimus (n:16, 28.6%), other angiogenesis inhibitors (n:4, 7.1%) TTF and OS from subsequent systemic therapy after cabozantinib failure were 2.8 months (95%CI 1.9-3.7) and 7.7 months (95%CI 4.4-10.8), respectively. ORR was 8.7% and 2 patients with axitinib and 2 patients treated with Immune checkpoint inhibitors achieved a partial response., Conclusion: Overall, activity of systemic therapies after cabozantinib was limited., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2022
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26. The Effect of Concomitant Proton Pump Inhibitor and Cabozantinib on the Outcomes of Patients with Metastatic Renal Cell Carcinoma.
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Rassy E, Cerbone L, Auclin E, Benchimoll-Zouari A, Flippot R, Alves Costa Silva C, Colomba E, Geraud A, Guida A, Mir O, Combarel D, Paci A, Escudier B, and Albiges L
- Subjects
- Anilides, Humans, Proton Pump Inhibitors therapeutic use, Pyridines, Retrospective Studies, Carcinoma, Renal Cell drug therapy, Kidney Neoplasms drug therapy
- Abstract
Introduction: Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC., Materials and Methods: This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry-liquid chromatography method., Results: We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups., Conclusion: In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC., Implications for Practice: Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context., (© 2021 AlphaMed Press.)
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- 2021
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27. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade.
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Ferrere G, Tidjani Alou M, Liu P, Goubet AG, Fidelle M, Kepp O, Durand S, Iebba V, Fluckiger A, Daillère R, Thelemaque C, Grajeda-Iglesias C, Alves Costa Silva C, Aprahamian F, Lefevre D, Zhao L, Ryffel B, Colomba E, Arnedos M, Drubay D, Rauber C, Raoult D, Asnicar F, Spector T, Segata N, Derosa L, Kroemer G, and Zitvogel L
- Subjects
- 3-Hydroxybutyric Acid administration & dosage, 3-Hydroxybutyric Acid metabolism, Animals, CTLA-4 Antigen antagonists & inhibitors, Cell Line, Tumor, Combined Modality Therapy, Female, Gastrointestinal Microbiome immunology, Humans, Immune Checkpoint Inhibitors administration & dosage, Ketone Bodies metabolism, Kidney Neoplasms diet therapy, Kidney Neoplasms drug therapy, Kidney Neoplasms immunology, Melanoma, Experimental diet therapy, Melanoma, Experimental drug therapy, Melanoma, Experimental immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasms, Experimental immunology, Receptors, G-Protein-Coupled antagonists & inhibitors, Diet, Ketogenic, Ketone Bodies administration & dosage, Neoplasms, Experimental diet therapy, Neoplasms, Experimental drug therapy, Programmed Cell Death 1 Receptor antagonists & inhibitors
- Abstract
Limited experimental evidence bridges nutrition and cancer immunosurveillance. Here, we show that ketogenic diet (KD) - or its principal ketone body, 3-hydroxybutyrate (3HB), most specifically in intermittent scheduling - induced T cell-dependent tumor growth retardation of aggressive tumor models. In conditions in which anti-PD-1 alone or in combination with anti-CTLA-4 failed to reduce tumor growth in mice receiving a standard diet, KD, or oral supplementation of 3HB reestablished therapeutic responses. Supplementation of KD with sucrose (which breaks ketogenesis, abolishing 3HB production) or with a pharmacological antagonist of the 3HB receptor GPR109A abolished the antitumor effects. Mechanistically, 3HB prevented the immune checkpoint blockade-linked upregulation of PD-L1 on myeloid cells, while favoring the expansion of CXCR3+ T cells. KD induced compositional changes of the gut microbiota, with distinct species such as Eisenbergiella massiliensis commonly emerging in mice and humans subjected to carbohydrate-low diet interventions and highly correlating with serum concentrations of 3HB. Altogether, these results demonstrate that KD induces a 3HB-mediated antineoplastic effect that relies on T cell-mediated cancer immunosurveillance.
- Published
- 2021
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28. Gut Bacteria Composition Drives Primary Resistance to Cancer Immunotherapy in Renal Cell Carcinoma Patients.
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Derosa L, Routy B, Fidelle M, Iebba V, Alla L, Pasolli E, Segata N, Desnoyer A, Pietrantonio F, Ferrere G, Fahrner JE, Le Chatellier E, Pons N, Galleron N, Roume H, Duong CPM, Mondragón L, Iribarren K, Bonvalet M, Terrisse S, Rauber C, Goubet AG, Daillère R, Lemaitre F, Reni A, Casu B, Alou MT, Alves Costa Silva C, Raoult D, Fizazi K, Escudier B, Kroemer G, Albiges L, and Zitvogel L
- Subjects
- Animals, Humans, Mice, Predictive Value of Tests, Prospective Studies, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell microbiology, Drug Resistance, Neoplasm, Feces microbiology, Gastrointestinal Microbiome, Immune Checkpoint Inhibitors therapeutic use, Kidney Neoplasms drug therapy, Kidney Neoplasms microbiology, Nivolumab therapeutic use
- Abstract
Background: The development of immune checkpoint blockade (ICB) has revolutionized the clinical outcome of renal cell carcinoma (RCC). Nevertheless, improvement of durability and prediction of responses remain unmet medical needs. While it has been recognized that antibiotics (ATBs) decrease the clinical activity of ICB across various malignancies, little is known about the direct impact of distinct intestinal nonpathogenic bacteria (commensals) on therapeutic outcomes of ICB in RCC., Objective: To evaluate the predictive value of stool bacteria composition for ICB efficacy in a cohort of advanced RCC patients., Design, Setting, and Participants: We prospectively collected fecal samples from 69 advanced RCC patients treated with nivolumab and enrolled in the GETUG-AFU 26 NIVOREN microbiota translational substudy phase 2 trial (NCT03013335) at Gustave Roussy. We recorded patient characteristics including ATB use, prior systemic therapies, and response criteria. We analyzed 2994 samples of feces from healthy volunteers (HVs). In parallel, preclinical studies performed in RCC-bearing mice that received fecal transplant (FMT) from RCC patients resistant to ICB (NR-FMT) allowed us to draw a cause-effect relationship between gut bacteria composition and clinical outcomes for ICB. The influence of tyrosine kinase inhibitors (TKIs) taken before starting nivolumab on the microbiota composition has also been assessed., Outcome Measurements and Statistical Analysis: Metagenomic data (MG) from whole genome sequencing (WGS) were analyzed by multivariate and pairwise comparisons/fold ratio to identify bacterial fingerprints related to ATB or prior TKI exposure and patients' therapeutic response (overall response and progression-free survival), and compared with the data from cancer-free donors., Results and Limitations: Recent ATB use (n = 11; 16%) reduced objective response rates (from 28% to 9%, p < 0.03) and markedly affected the composition of the microbiota, facilitating the dominance of distinct species such as Clostridium hathewayi, which were also preferentially over-represented in stools from RCC patients compared with HVs. Importantly, TKIs taken prior to nivolumab had implications in shifting the microbiota composition. To establish a cause-effect relationship between gut bacteria composition and ICB efficacy, NR-FMT mice were successfully compensated with either FMT from responding RCC patients or beneficial commensals identified by WGS-MG (Akkermansia muciniphila and Bacteroides salyersiae)., Conclusions: The composition of the microbiota is influenced by TKIs and ATBs, and impacts the success of immunotherapy. Future studies will help sharpen the role of these specific bacteria and their potential as new biomarkers., Patient Summary: We used quantitative shotgun DNA sequencing of fecal microbes as well as preclinical models of fecal or bacterial transfer to study the association between stool composition and (pre)clinical outcome to immune checkpoint blockade. Novel insights into the pathophysiological relevance of intestinal dysbiosis in the prognosis of kidney cancer may lead to innovative therapeutic solutions, such as supplementation with probiotics to prevent primary resistance to therapy., (Copyright © 2020. Published by Elsevier B.V.)
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- 2020
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29. Elucidating the gut microbiota composition and the bioactivity of immunostimulatory commensals for the optimization of immune checkpoint inhibitors.
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Daillère R, Routy B, Goubet AG, Cogdill A, Ferrere G, Alves-Costa Silva C, Fluckiger A, Ly P, Haddad Y, Pizzato E, Thelemaque C, Fidelle M, Mazzenga M, Roberti MP, Melenotte C, Liu P, Terrisse S, Kepp O, Kroemer G, Zitvogel L, and Derosa L
- Subjects
- Dysbiosis, Humans, Immune Checkpoint Inhibitors, Symbiosis, Gastrointestinal Microbiome, Neoplasms drug therapy
- Abstract
Accumulating evidence from preclinical studies and human trials demonstrated the crucial role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade. In summary, it appears that a diverse intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota composition that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. In this review, we explore preclinical and translational studies highlighting how eubiotic and dysbiotic microbiota composition can affect progression-free survival in cancer patients., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)
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- 2020
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30. Combination treatments with hydroxychloroquine and azithromycin are compatible with the therapeutic induction of anticancer immune responses.
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Liu P, Zhao L, Ferrere G, Alves-Costa-Silva C, Ly P, Wu Q, Tian AL, Derosa L, Zitvogel L, Kepp O, and Kroemer G
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Azithromycin pharmacokinetics, COVID-19 immunology, COVID-19 virology, Cell Line, Tumor, Cisplatin administration & dosage, Cisplatin pharmacokinetics, Clinical Trials, Phase II as Topic, Crizotinib administration & dosage, Crizotinib pharmacokinetics, Disease Models, Animal, Drug Evaluation, Preclinical, Drug Interactions, Drug Therapy, Combination methods, Female, France, Humans, Hydroxychloroquine pharmacokinetics, Mice, Neoplasms immunology, Oxaliplatin administration & dosage, Oxaliplatin pharmacokinetics, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, SARS-CoV-2 immunology, SARS-CoV-2 isolation & purification, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Azithromycin administration & dosage, Hydroxychloroquine administration & dosage, Neoplasms drug therapy, COVID-19 Drug Treatment
- Abstract
Amid controversial reports that COVID-19 can be treated with a combination of the antimalarial drug hydroxychloroquine (HCQ) and the antibiotic azithromycin (AZI), a clinical trial (ONCOCOVID, NCT04341207) was launched at Gustave Roussy Cancer Campus to investigate the utility of this combination therapy in cancer patients. In this preclinical study, we investigated whether the combination of HCQ+AZI would be compatible with the therapeutic induction of anticancer immune responses. For this, we used doses of HCQ and AZI that affect whole-body physiology (as indicated by a partial blockade in cardiac and hepatic autophagic flux for HCQ and a reduction in body weight for AZI), showing that their combined administration did not interfere with tumor growth control induced by the immunogenic cell death inducer oxaliplatin. Moreover, the HCQ+AZI combination did not affect the capacity of a curative regimen (cisplatin + crizotinib + PD-1 blockade) to eradicate established orthotopic lung cancers in mice. In conclusion, it appears that HCQ+AZI does not interfere with the therapeutic induction of therapeutic anticancer immune responses., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)
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- 2020
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31. New pathways in immune stimulation: targeting OX40.
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Alves Costa Silva C, Facchinetti F, Routy B, and Derosa L
- Subjects
- Humans, Immunotherapy methods, Neoplasms immunology, Receptors, OX40 therapeutic use
- Abstract
Immune checkpoint blockers (ICB) reinvigorate the immune system by removing the molecular brakes responsible for the scarce activity of immune phenotypes against malignant cells. After having proven their remarkable role as monotherapy, combinations of anti-Programmed cell death 1 (PD-1)/Programmed death-ligand 1 (PD-L1) agents with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies, chemotherapy and/or anti-angiogenic compounds provide unprecedented results and durable responses across a variety of tumour types. Nevertheless, the main drawbacks of ICB are represented by primary and acquired resistance, translating into disease progression, as well as by immune-related toxicities. In this sense, novel strategies to foster the immune system through its direct stimulation are being tested in order to provide additional clinical improvements in patients with cancer. In this scenario, the co-stimulatory molecule OX40 (CD134) belongs to the next generation of immune therapeutic targets. Preliminary results of early clinical trials evaluating OX40 stimulation by means of different agents are encouraging. Here we review the rationale of OX40 targeting, highlighting the combination of OX40-directed therapies with different anticancer agents as a potential strategy to foster the immune system against malignant phenotypes., Competing Interests: Competing interests: None declared., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)
- Published
- 2020
- Full Text
- View/download PDF
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