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1. Personalized cancer therapy prioritization based on driver alteration co-occurrence patterns

Author

Pedram Razavi, Patrick Aloy, Maurizio Scaltriti, Lidia Mateo, Miquel Duran-Frigola, Joaquín Arribas, Meritxell Bellet, Sarat Chandarlapaty, Marta Palafox, Albert Gris-Oliver, Violeta Serra, Institut Català de la Salut, [Mateo L, Duran-Frigola M] Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Catalonia, Spain. [Gris-Oliver A, Palafox M] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Scaltriti M] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Department of Pathology, MSKC C, New York, NY 10065, USA. [Razavi P] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Breast Medicine Service, Department of Medicine, MSKCC and Weill-Cornell Medical College, New York, NY 10065, USA. [Arribas J] Growth Factors Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. CIBERONC, Barcelona, Spain. [Bellet M] Breast Cancer Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Serra V] Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. CIBERONC, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Genomic profiling, Databases, Factual, Oncologia, Computer science, Method, lcsh:Medicine, Genome, Translational Research, Biomedical, Drug-response biomarkers, 0302 clinical medicine, Survival data, terapéutica::medicina de precisión [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Neoplasms, Profiling (information science), Medicina personalitzada, Precision Medicine, Genetics (clinical), Otros calificadores::/terapia [Otros calificadores], 0303 health sciences, Càncer - Tractament, Disease Management, Precision oncology, Genomics, 3. Good health, Gene Expression Regulation, Neoplastic, Identification (information), Treatment Outcome, 030220 oncology & carcinogenesis, Biomarker (medicine), Molecular Medicine, Càncer -- Tractament, Therapeutics::Precision Medicine [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Algorithms, Prioritization, lcsh:QH426-470, Systems biology, Clinical Decision-Making, Cancer therapy, Antineoplastic Agents, Computational biology, neoplasias [ENFERMEDADES], 03 medical and health sciences, In vivo, Biomarkers, Tumor, medicine, Genetics, Humans, Tumor growth, Progression-free survival, Molecular Biology, 030304 developmental biology, lcsh:R, Co-occurrence, Reproducibility of Results, Cancer, Oncogenes, Other subheadings::/therapy [Other subheadings], Models, Theoretical, medicine.disease, Human genetics, Clinical trial, Neoplasms [DISEASES], lcsh:Genetics, Genòmica, Drug Resistance, Neoplasm, Driver co-occurrence networks
Abstract

Molecular profiling of personal cancer genomes, and the identification of actionable vulnerabilities and drug-response biomarkers, are the basis of precision oncology. Tumors often present several driver alterations that might be connected by cross-talk and feedback mechanisms, making it difficult to mark single oncogenic variations as reliable predictors of therapeutic outcome. In the current work, we uncover and exploit driver alteration co-occurrence patterns from a recently published in vivo screening in patient-derived xenografts (PDXs), including 187 tumors and 53 drugs. For each treatment, we compare the mutational profiles of sensitive and resistant PDXs to statistically define Driver Co-Occurrence (DCO) networks, which capture both genomic structure and putative oncogenic synergy. We then use the DCO networks to train classifiers that can prioritize, among the available options, the best possible treatment for each tumor based on its oncogenomic profile. In a cross-validation setting, our drug-response models are able to correctly predict 66% of sensitive and 77% of resistant drug-tumor pairs, based on tumor growth variation. Perhaps more interesting, our models are applicable to several tumor types and drug classes for which no biomarker has yet been described. Additionally, we experimentally validated the performance of our models on 15 new tumor samples engrafted in mice, achieving an overall accuracy of 75%. Finally, we adapted our strategy to derive drug-response models from continuous clinical outcome measures, such as progression free survival, which better represent the data acquired during routine clinical practice and in clinical trials. We believe that the computational framework presented here could be incorporated into the design of adaptive clinical trials, revealing unexpected connections between oncogenic alterations and increasing the clinical impact of genomic profiling.

Published
2020

2. Emerging and Evolving Concepts in Cancer Immunotherapy Imaging

Author

Laurent Dercle, Shawn Sun, Romain-David Seban, Ahmed Mekki, Roger Sun, Lambros Tselikas, Sophie Hans, Alice Bernard-Tessier, Fadila Mihoubi Bouvier, Nicolas Aide, Laetitia Vercellino, Alexia Rivas, Antoine Girard, Fatima-Zohra Mokrane, Guillaume Manson, Roch Houot, Egesta Lopci, Randy Yeh, Samy Ammari, Lawrence H. Schwartz, Columbia University Medical Center (CUMC), Columbia University [New York], Institut Curie [Paris], Hôpital Raymond Poincaré [AP-HP], Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, TheraPanacea [Paris], Institut Gustave Roussy (IGR), Département d'imagerie médicale [Gustave Roussy], CHU Henri Mondor [Créteil], Département d’Innovation Thérapeutique et essais précoces [Gustave Roussy] (DITEP), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Centre Eugène Marquis (CRLCC), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humanitas Clinical and Research Center [Rozzano, Milan, Italy], Memorial Sloan Kettering Cancer Center (MSKCC), Fondation ARC pour la recherche médicale (international mobility grant and grant SIGN’IC20161236437), INSERM, and Fondation Bettencourt Schueller, pending U.S. patent (no. 16630031), and Fondazione AIRC

Subjects
[SDV]Life Sciences [q-bio], CLINICAL BENEFIT, NIVOLUMAB, MELANOMA, ASSOCIATION, HYPERPROGRESSIVE DISEASE, GUIDELINES, Neoplasms, Positron-Emission Tomography, Disease Progression, Humans, Immunologic Factors, CRITERIA, Radiology, Nuclear Medicine and imaging, Immunotherapy, IMMUNE-RELATED RESPONSE, ADVERSE EVENTS, INHIBITORS
Abstract

International audience; Criteria based on measurements of lesion diameter at CT have guided treatment with historical therapies due to the strong association between tumor size and survival. Clinical experience with immune checkpoint modulators shows that editing immune system function can be effective in various solid tumors. Equally, novel immune-related phenomena accompany this novel therapeutic paradigm. These effects of immunotherapy challenge the association of tumor size with response or progression and include risks and adverse events that present new demands for imaging to guide treatment decisions. Emerging and evolving approaches to immunotherapy highlight further key issues for imaging evaluation, such as dissociated response following local administration of immune checkpoint modulators, pseudoprogression due to immune infiltration in the tumor environment, and premature death due to hyperprogression. Research that may offer tools for radiologists to meet these challenges is reviewed. Different modalities are discussed, including immuno-PET, as well as new applications of CT, MRI, and fluorodeoxyglucose PET, such as radiomics and imaging of hematopoietic tissues or anthropometric characteristics. Multilevel integration of imaging and other biomarkers may improve clinical guidance for immunotherapies and provide theranostic opportunities.

Published
2023
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3. Inactivation of AMPK Leads to Attenuation of Antigen Presentation and Immune Evasion in Lung Adenocarcinoma

Author

Emmy W. Verschuren, Pekka Paivinen, Sushil Tripathi, Ashwini S. Nagaraj, Eva Domenech-Moreno, Tomi P. Mäkelä, Kari Vaahtomeri, Iris P. L. Wong, Sarang S. Talwelkar, Marc Foretz, Benoit Viollet, Yan Yan, Yajing Gao, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Memorial Sloan Kettering Cancer Center (MSKCC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), FORETZ, Marc, University of Helsinki, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, Lung Neoplasms, medicine.medical_treatment, Antigen presentation, STK11, Adenocarcinoma of Lung, AMP-Activated Protein Kinases, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Carcinoma, Non-Small-Cell Lung, Tumor Microenvironment, medicine, Animals, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], skin and connective tissue diseases, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Immune Evasion, 030304 developmental biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Antigen Presentation, 0303 health sciences, AMPK, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Immunotherapy, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Oncology, 030220 oncology & carcinogenesis, Cancer research, KRAS, Carcinogenesis, CD8
Abstract

Purpose: Mutations in STK11 (LKB1) occur in 17% of lung adenocarcinoma (LUAD) and drive a suppressive (cold) tumor immune microenvironment (TIME) and resistance to immunotherapy. The mechanisms underpinning the establishment and maintenance of a cold TIME in LKB1-mutant LUAD remain poorly understood. In this study, we investigated the role of the LKB1 substrate AMPK in immune evasion in human non—small cell lung cancer (NSCLC) and mouse models and explored the mechanisms involved. Experimental Design: We addressed the role of AMPK in immune evasion in NSCLC by correlating AMPK phosphorylation and immune-suppressive signatures and by deleting AMPKα1 (Prkaa1) and AMPKα2 (Prkaa2) in a KrasG12D-driven LUAD. Furthermore, we dissected the molecular mechanisms involved in immune evasion by comparing gene-expression signatures, AMPK activity, and immune infiltration in mouse and human LUAD and gain or loss-of-function experiments with LKB1- or AMPK-deficient cell lines. Results: Inactivation of both AMPKα1 and AMPKα2 together with Kras activation accelerated tumorigenesis and led to tumors with reduced infiltration of CD8+/CD4+ T cells and gene signatures associated with a suppressive TIME. These signatures recapitulate those in Lkb1-deleted murine LUAD and in LKB1-deficient human NSCLC. Interestingly, a similar signature is noted in human NSCLC with low AMPK activity. In mechanistic studies, we find that compromised LKB1 and AMPK activity leads to attenuated antigen presentation in both LUAD mouse models and human NSCLC. Conclusions: The results provide evidence that the immune evasion noted in LKB1-inactivated lung cancer is due to subsequent inactivation of AMPK and attenuation of antigen presentation.

Published
2022
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4. Phase 1/2 study of intratumoral G100 (TLR4 agonist) with or without pembrolizumab in follicular lymphoma

Author

Ahmad S. Halwani, Carlos Panizo, Iris Isufi, Alex F. Herrera, Craig Y. Okada, Elizabeth H. Cull, Bela Kis, Jorge M. Chaves, Nancy L. Bartlett, Weiyun Ai, Luis de la Cruz-Merino, Locke J. Bryan, Roch Houot, Kim Linton, Javier Briones, Ian Chau, Gottfried R. von Keudell, Hailing Lu, Adam Yakovich, Michael Chen, ter Meulen JH, Sergey Yurasov, Frank J. Hsu, Christopher R. Flowers, University of Utah, Clínica Universidad de Navarra [Pamplona], Universidad de Navarra [Pamplona] (UNAV), Yale University School of Medicine, H. Lee Moffitt Cancer Center and Research Institute, North-West University [Potchefstroom] (NWU), University of California [San Francisco] (UCSF), University of California, University of Sevilla, Augusta University, University System of Georgia (USG), CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Manchester University NHS Foundation Trust (MFT), Memorial Sloan Kettering Cancer Center (MSKCC), The University of Texas M.D. Anderson Cancer Center [Houston], Emory University [Atlanta, GA], Immune Design Corp., Yale School of Medicine [New Haven, Connecticut] (YSM), University of California [San Francisco] (UC San Francisco), University of California (UC), Universidad de Sevilla / University of Sevilla, and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
0303 health sciences, Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematology, Antibodies, Monoclonal, Humanized, 3. Good health, Toll-Like Receptor 4, 03 medical and health sciences, 0302 clinical medicine, follicular lymphoma, Oncology, glucopyranosyl lipid A, 030220 oncology & carcinogenesis, Antineoplastic Combined Chemotherapy Protocols, Humans, TLR4, immunotherapy, pembrolizumab, Lymphoma, Follicular, 030304 developmental biology
Abstract

International audience; Intratumoral injection of G100, a toll-like receptor 4 (TLR4) agonist, was shown pre-clinically to stimulate anti-tumor immune responses and tumor regression. This open-label, multicenter, phase 1/2 trial evaluated the safety, tolerability, and preliminary efficacy of intratumoral G100 injections following localized low-dose radiation in patients with follicular lymphoma (ClinicalTrials.gov #NCT02501473). The study was comprised of a G100 dose escalation (5 or 10 mu g/dose, or 20 mu g/dose for large tumors); a randomized component comparing G100 to G100 plus pembrolizumab; and G100 20 mu g/dose expansion. Adverse events grade >= 3 were uncommon in patients treated with G100, and no unexpected toxicities were observed when combined with pembrolizumab. G100 20 mu g (n = 18) resulted in an overall response rate of 33.3% and abscopal tumor regression in 72.2% of patients. This early-phase study provides a foundation for combining an intratumoral TLR4 agonist with agents to produce immune-mediated responses in follicular lymphoma with limited added toxicity.

Published
2021
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5. Consensus guidelines for the definition of time-to-event end points in image-guided tumor ablation

Author

Puijk, Robbert, Ahmed, Muneeb, Adam, Andreas, Arai, Yasuaki, Arellano, Ronald, de Baère, Thierry, Bale, Reto, Bellera, Carine, Binkert, Christoph, Brace, Christopher, Breen, David, Brountzos, Elias, Callstrom, Matthew, Carrafiello, Gianpaolo, Chapiro, Julius, de Cobelli, Francesco, Coupé, Veerle, Crocetti, Laura, Denys, Alban, Dupuy, Damian, Erinjeri, Joseph, Filippiadis, Dimitris, Gangi, Afshin, Gervais, Debra, Gillams, Alice, Greene, Tissy, Guiu, Boris, Helmberger, Thomas, Iezzi, Roberto, Kang, Tae Wook, Kelekis, Alexis, Kim, Hyun, Kröncke, Thomas, Kwan, Sharon, Lee, Min Woo, Lee, Fred, Lee, Edward, Liang, Ping, Lissenberg-Witte, Birgit, Lu, David, Madoff, David, Mauri, Giovanni, Meloni, Maria Franca, Morgan, Robert, Nadolski, Gregory, Narayanan, Govindarajan, Newton, Isabel, Nikolic, Boris, Orsi, Franco, Pereira, Philippe, Pua, Uei, Rhim, Hyunchul, Ricke, Jens, Rilling, William, Salem, Riad, Scheffer, Hester, Sofocleous, Constantinos, Solbiati, Luigi, Solomon, Stephen, Soulen, Michael, Sze, Daniel, Uberoi, Raman, Vogl, Thomas, Wang, David, Wood, Bradford, Goldberg, S Nahum, Meijerink, Martijn, Goldberg, S. Nahum, Amsterdam UMC - Amsterdam University Medical Center, Harvard Medical School [Boston] (HMS), Guy's and St Thomas' Hospital [London], National Cancer Center Hospital (NCCJ), Department of radiology (Massachusetts General Hospital), Massachusetts General Hospital [Boston], Institut Gustave Roussy (IGR), Imagerie thérapeutique (radiologie interventionnelle), Département d'imagerie médicale [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Institut Bergonié [Bordeaux], UNICANCER, Kantonsspital Winterthur (KSW), University of Wisconsin School of Medicine and Public Health, University Hospital Southampton NHS Foundation Trust, National and Kapodistrian University of Athens (NKUA), Mayo Clinic [Rochester], Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Yale University [New Haven], IRCCS Ospedale San Raffaele [Milan, Italy], Vrije Universiteit Medical Centre (VUMC), Vrije Universiteit Amsterdam [Amsterdam] (VU), University of Pisa - Università di Pisa, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Warren Alpert Medical School of Brown University, Memorial Sloan Kettering Cancer Center (MSKCC), L'Institut hospitalo-universitaire de Strasbourg (IHU Strasbourg), Institut National de Recherche en Informatique et en Automatique (Inria)-l'Institut de Recherche contre les Cancers de l'Appareil Digestif (IRCAD)-Les Hôpitaux Universitaires de Strasbourg (HUS)-La Fédération des Crédits Mutuels Centre Est (FCMCE)-L'Association pour la Recherche contre le Cancer (ARC)-La société Karl STORZ, The London Clinic cancer, Society of Interventional Oncology (SIO), Service de radiologie et d'Imagerie médicale diagnostique et thérapeutique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), and Kiel University

Subjects
Ablation Techniques, medicine.medical_specialty, Consensus, [SDV]Life Sciences [q-bio], MESH: Societies, Medical, MEDLINE, Outcome (game theory), Session (web analytics), Quality of life (healthcare), Humans, Neoplasms, Reproducibility of Results, Societies, Medical, Medical, medicine, MESH: Neoplasms, Radiology, Nuclear Medicine and imaging, Medical physics, ddc:610, MESH: Consensus, License, MESH: Humans, Health economics, business.industry, MESH: Ablation Techniques, Opinion leadership, MESH: Reproducibility of Results, Clinical trial, business, Societies
Abstract

International audience; There is currently no consensus regarding preferred clinical outcome measures following image-guided tumor ablation or clear definitions of oncologic end points. This consensus document proposes standardized definitions for a broad range of oncologic outcome measures with recommendations on how to uniformly document, analyze, and report outcomes. The initiative was coordinated by the Society of Interventional Oncology in collaboration with the Definition for the Assessment of Time-to-Event End Points in Cancer Trials, or DATECAN, group. According to predefined criteria, based on experience with clinical trials, an international panel of 62 experts convened. Recommendations were developed using the validated three-step modified Delphi consensus method. Consensus was reached on when to assess outcomes per patient, per session, or per tumor; on starting and ending time and survival time definitions; and on time-to-event end points. Although no consensus was reached on the preferred classification system to report complications, quality of life, and health economics issues, the panel did agree on using the most recent version of a validated patient-reported outcome questionnaire. This article provides a framework of key opinion leader recommendations with the intent to facilitate a clear interpretation of results and standardize worldwide communication. Widespread adoption will improve reproducibility, allow for accurate comparisons, and avoid misinterpretations in the field of interventional oncology research. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

Published
2021
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6. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study

Author

Deepa Jeyakumar, Ryan D. Cassaday, Roch Houot, Chaoling Feng, Dimitrios Tzachanis, Maria R. Baer, John M. Rossi, Patrick J. Stiff, Marion Subklewe, Max S. Topp, Behzad Kharabi Masouleh, Bijal D. Shah, Remus Vezan, Martha Arellano, Olalekan O. Oluwole, Aaron C Logan, William G. Wierda, Kristen M. O'Dwyer, Tong Shen, Monique C. Minnema, Jinghui Dong, Daniel J. DeAngelo, Nicolas Boissel, Mehrdad Abedi, Francesca Milletti, Gary J. Schiller, Thibaut Leguay, Armin Ghobadi, Michael R. Bishop, Yi Lin, Jae H. Park, H. Lee Moffitt Cancer Center and Research Institute, Washington University in Saint Louis (WUSTL), Vanderbilt University [Nashville], Helen Diller Family Comprehensive Cancer Center [San Francisco], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Washington [Seattle], CHU Bordeaux [Bordeaux], The University of Chicago Medicine [Chicago], University Hospital of Würzburg, University of California [San Diego] (UC San Diego), University of California, Mayo Clinic [Rochester], University of Rochester [USA], Emory University [Atlanta, GA], University of Maryland [Baltimore], David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, State University of New York at New Paltz (SUNY New Paltz), State University of New York (SUNY), Memorial Sloan Kettering Cancer Center (MSKCC), Ludwig-Maximilians-Universität München (LMU), California State University [Sacramento], University Medical Center [Utrecht], The University of Texas M.D. Anderson Cancer Center [Houston], Dana-Farber Cancer Institute [Boston], Loyola University [Chicago], University of California [Irvine] (UCI), Kite (Gilead), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], University of California (UC), University of California (UC)-University of California (UC), University of California [Irvine] (UC Irvine), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
Adult, Male, medicine.medical_specialty, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Population, 030204 cardiovascular system & hematology, Immunotherapy, Adoptive, 03 medical and health sciences, 0302 clinical medicine, Refractory, Recurrence, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Internal medicine, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, education, Survival analysis, Aged, Chemotherapy, education.field_of_study, Receptors, Chimeric Antigen, business.industry, General Medicine, Leukapheresis, Middle Aged, Survival Analysis, Minimal residual disease, 3. Good health, Clinical trial, Treatment Outcome, Female, business
Abstract

International audience; BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 10(6) CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p

Published
2021
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7. Systematically higher Ki67 scores on core biopsy samples compared to corresponding resection specimen in breast cancer: a multi-operator and multi-institutional study

Author

Balazs Acs, Samuel C.Y. Leung, Kelley M. Kidwell, Indu Arun, Renaldas Augulis, Sunil S. Badve, Yalai Bai, Anita L. Bane, John M.S. Bartlett, Jane Bayani, Gilbert Bigras, Annika Blank, Henk Buikema, Martin C. Chang, Robin L. Dietz, Andrew Dodson, Susan Fineberg, Cornelia M. Focke, Dongxia Gao, Allen M. Gown, Carolina Gutierrez, Johan Hartman, Zuzana Kos, Anne-Vibeke Lænkholm, Arvydas Laurinavicius, Richard M. Levenson, Rustin Mahboubi-Ardakani, Mauro G. Mastropasqua, Sharon Nofech-Mozes, C. Kent Osborne, Frédérique M. Penault-Llorca, Tammy Piper, Mary Anne Quintayo, Tilman T. Rau, Stefan Reinhard, Stephanie Robertson, Roberto Salgado, Tomoharu Sugie, Bert van der Vegt, Giuseppe Viale, Lila A. Zabaglo, Daniel F. Hayes, Mitch Dowsett, Torsten O. Nielsen, David L. Rimm, Lisa M. McShane, Torsten Nielsen, Samuel Leung, Signe Borgquist, Angela Chan, Carsten Denkert, Anna Ehinger, Matthew Ellis, Margaret Flowers, Chad Galderisi, Abhi Gholap, Douglas J. Hartman, Judith C. Hugh, Anagha Jadhav, Elizabeth N. Kornaga, Hans Kreipe, Richard Levenson, Mauro Mastropasqua, Takuya Moriya, Hongchao Pan, Liron Pantanowitz, Ernesta Paola Neri, Mei-Yin Polley, Jason Ruan, Takashi Sakatani, Lois Shepherd, Ian Smith, Joseph Sparano, Melanie Spears, Malini Srinivasan, Jane Starczynski, Austin Todd, Shakeel Virk, Yihong Wang, Hua Yang, Zhiwei Zhang, Inti Zlobec, Rigshospitalet [Copenhagen], Copenhagen University Hospital, CHUV, Lausanne (Departement d'Oncologie), St Jude Children's Research Hospital, Laboratorio de Dianas Terapeuticas, Centro Integral Oncologico Clara Campal, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Washington [Seattle], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Institut Gustave Roussy (IGR), Direction de la recherche clinique [Gustave Roussy], Memorial Sloan Kettering Cancer Center (MSKCC), Weill Medical College of Cornell University [New York], Sylvester Comprehensive Cancer Center [Miami, FL, USA] (S3C), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)

Subjects
[SDV]Life Sciences [q-bio], Biopsy, Image Processing, DIGITAL-IMAGE-ANALYSIS, MULTICENTER, Medical and Health Sciences, MESH: Biopsy, Computer-Assisted, REPRODUCIBILITY, NEEDLE BIOPSIES, Receptors, Image Processing, Computer-Assisted, Pathology, MESH: Protein Kinase Inhibitors, 610 Medicine & health, Cancer, Tumor, PROLIFERATION, MESH: Receptor, trkA, KI-67 LABELING INDEX, MESH: Image Processing, Computer-Assisted, Immunohistochemistry, INTERNATIONAL KI67, Receptors, Estrogen, TRK fusion, RELIABILITY, MESH: Receptors, Estrogen, Female, MESH: Biomarkers, Tumor, NTRK gene fusions, MESH: Ki-67 Antigen, International Ki67 in Breast Cancer Working Group of the Breast International Group and North American Breast Cancer Group, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Settore MED/08 - Anatomia Patologica, Non-interventional study, Pathology and Forensic Medicine, Clinical Research, Biomarkers, Tumor, Humans, Ki-67 Antigen, Breast Cancer, BIOMARKER ASSESSMENT, Larotrectinib, MESH: Humans, MESH: Immunohistochemistry, Estrogen, MESH: Pyrimidines, 570 Life sciences, biology, MESH: Female, MESH: Pyrazoles, MESH: Breast Neoplasms, Biomarkers
Abstract

International audience; Abstract Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error ( p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections ( p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.; v2.5, 25 March 2021.

Published
2022
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8. Rationale and design of ON-TRK:a novel prospective non-interventional study in patients with TRK fusion cancer treated with larotrectinib

Author

James C. H. Yang, Marcia S. Brose, Gilberto Castro, Edward S. Kim, Ulrik N. Lassen, Serge Leyvraz, Alberto Pappo, Fernando López-Ríos, John A. Reeves, Marc Fellous, Frédérique Penault-Llorca, Erin R. Rudzinski, Ghazaleh Tabatabai, Gilles Vassal, Alexander Drilon, Jonathan Trent, National Taiwan University Cancer Center [Taipei], Abramson Cancer Center [philadelphia], University of Pennsylvania-Perelman School of Medicine, University of Pennsylvania, Instituto do Câncer do Estado = Cancer Institute of the State of São Paulo (ICESP), Levine Cancer Institute, Atrium Health [Charlotte, NC, USA] (LCIAH), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], St Jude Children's Research Hospital, Hospital Universitario HM Sanchinarro [Madrid, Spain], Bayer HealthCare Pharmaceuticals Inc [Whippany], Bayer HealthCare Pharmaceuticals, Inc. [Basel, Switzerland] (BHCP), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Washington [Seattle], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Institut Gustave Roussy (IGR), Direction de la recherche [Gustave Roussy], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Sylvester Comprehensive Cancer Center [Miami, FL, USA] (S3C), Malbec, Odile, The Levine Cancer Institute, Direction de la recherche clinique [Gustave Roussy], and Memorial Sloan Kettering Cancer Center (MSKCC)

Subjects
Adult, Cancer Research, Oncogene Proteins, Fusion, [SDV]Life Sciences [q-bio], Fibrosarcoma, Neoplasms, Second Primary, Non-interventional study, [SDV] Life Sciences [q-bio], Pyrimidines, Oncology, TRK fusion, Neoplasms, Genetics, Humans, Pyrazoles, Prospective Studies, Gene Fusion, Receptor, trkA, Child, Protein Kinase Inhibitors, NTRK gene fusions, Larotrectinib
Abstract

Background Tropomyosin receptor kinase (TRK) fusion proteins resulting from neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare primary oncogenic drivers in a wide array of tumors. Larotrectinib is a first-in-class, highly selective, central nervous system-active TRK inhibitor approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and over 40 countries for the treatment of TRK fusion solid tumors in adult and pediatric patients. Due to the rarity of TRK fusion cancer, larotrectinib was granted accelerated approval based on a relatively small number of patients enrolled in three early phase trials. ON-TRK aims to evaluate the safety profile of larotrectinib in a broader population and over extended time periods. Methods ON-TRK is a prospective, non-interventional, open-label, multicenter, multi-cohort, post-approval study in adult and pediatric patients with locally advanced or metastatic TRK fusion cancer treated with larotrectinib that will describe the safety and effectiveness of larotrectinib in real-world practice conditions. Adult patients will be grouped by tumor type and followed for at least 2 years. Patients Discussion The FDA Accelerated Approval Program allows for earlier approval of and patient access to drugs that treat serious conditions and fill an unmet medical need. This study is designed to fulfill post-approval requirements set by the FDA as well as post-marketing requirements set forth by local regulatory bodies and is part of the risk management plan for the EMA. Study registration This study is registered at ClinicalTrials.gov (NCT04142437). Protocol version v2.5, 25 March 2021.

Published
2022
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9. Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology

Author

Peter-Michael Rath, Methee Chayakulkeeree, Alessandro C. Pasqualotto, Christopher C. Kibbler, María José Buitrago, Thuy Le, Neil M Ampel, Flavio Queiroz-Telles, Ferry Hagen, Oliver A. Cornely, Paul E. Verweij, Ana Alastruey-Izquierdo, Ariya Chindamporn, Nelesh P. Govender, Carol A. Kauffman, Graeme Meintjes, Darius Armstrong-James, Chris Kenyon, Grégory Jouvion, Ilan S. Schwartz, Olusola Ayanlowo, Jean-Pierre Gangneux, John W Baddley, George Richard Thompson, Jasper Fuk-Woo Chan, David R. Andes, Tobias M. Hohl, Low Lee Lee, Andrej Spec, Cao Cun-wei, Robert Krause, Ebrahim Variava, Marisa H. Miceli, David C M Kong, Leili Chamani-Tabriz, Mohammad Taghi Hedayati, Bridget M. Barker, Nikolai Klimko, Leila Maria Lopes Bezerra, University of California [Davis] (UC Davis), University of California, Duke University [Durham], Chulalongkorn University [Bangkok], University of Michigan Medical School [Ann Arbor], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Instituto de Salud Carlos III [Madrid] (ISC), University of Arizona, University of Wisconsin-Madison, Imperial College London, University of Lagos, University of Maryland School of Medicine, University of Maryland System, The Pathogen and Microbiome Institute, Northern Arizona University [Flagstaff], State University of Rio de Janeiro, The University of Hong Kong (HKU), Mahidol University [Bangkok], University Hospital of Cologne [Cologne], Guangxi University [Nanning], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), National Institute for Communicable Diseases [Johannesburg] (NICD), University of the Witwatersrand [Johannesburg] (WITS), University Medical Center [Utrecht], Mazandaran University of Medical Sciences, Memorial Sloan Kettering Cancer Center (MSKCC), Neuropathologie expérimentale / Experimental neuropathology, Institut Pasteur [Paris]-Université de Paris (UP), Maladies génétiques d'expression pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Tropical Medicine [Antwerp] (ITM), University College of London [London] (UCL), University of Ballarat [Australie] (FedUni), Institute of Biophysics [Graz], Medical University Graz, University of Cape Town, Ruhrlandklinik University Hospital, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Federal University of Technology - Paraná (UTFPR), Radboud University Medical Center [Nijmegen], University of Alberta, Federal University of Health Sciences of Porto Alegre = Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), University of California (UC), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Maladies génétiques d'expression pédiatrique (U933), and Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP]

Subjects
medicine.medical_specialty, Consensus, Endemic Diseases, [SDV]Life Sciences [q-bio], International Cooperation, Clinical Sciences, Clinical Decision-Making, Medizin, MEDLINE, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Guidelines as Topic, Global Health, Microbiology, Article, Histoplasmosis, Vaccine Related, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Risk Factors, Biodefense, Mycology, Epidemiology, medicine, Animals, Humans, 030212 general & internal medicine, Intensive care medicine, 0303 health sciences, Sporotrichosis, 030306 microbiology, Paracoccidioidomycosis, business.industry, Prevention, Guideline, medicine.disease, 3. Good health, Europe, Emerging Infectious Diseases, Good Health and Well Being, Infectious Diseases, Mycoses, Medical Microbiology, Public Health and Health Services, Infection, business, Blastomycosis
Abstract

International audience; The global burden of the endemic mycoses (blastomycosis, coccidioidomycosis, emergomycosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and talaromycosis) continues to rise yearly and these infectious diseases remain a leading cause of patient morbidity and mortality worldwide. Management of the associated pathogens requires a thorough understanding of the epidemiology, risk factors, diagnostic methods and performance characteristics in different patient populations, and treatment options unique to each infection. Guidance on the management of these infections has the potential to improve prognosis. The recommendations outlined in this Review are part of the "One World, One Guideline" initiative of the European Confederation of Medical Mycology. Experts from 23 countries contributed to the development of these guidelines. The aim of this Review is to provide an up-to-date consensus and practical guidance in clinical decision making, by engaging physicians and scientists involved in various aspects of clinical management.

Published
2021
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10. Risk factors and a prognostic score for survival after autologous stem-cell transplantation for relapsed or refractory Hodgkin lymphoma

Author

M. Jürgens, Martin Hutchings, B. von Tresckow, Michael Fuchs, Peter Borchmann, Paul J Bröckelmann, S.J. McCall, Horst Müller, Craig H. Moskowitz, Andreas Engert, Franck Morschhauser, Olivier Casasnovas, University Hospital of Cologne [Cologne], Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Rigshospitalet [Copenhagen], Memorial Sloan Kettering Cancer Center ( MSKCC ), Service d'hématologie, Hôpital Claude Huriez-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Copenhagen University Hospital, Memorial Sloane Kettering Cancer Center [New York], Hôpital Claude Huriez [Lille], and CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Adult, Male, Oncology, medicine.medical_specialty, medicine.medical_treatment, Salvage therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, Autologous stem-cell transplantation, Recurrence, Internal medicine, Refractory Hodgkin Lymphoma, Humans, risk factors, score, Medicine, ASCT, Aged, Proportional Hazards Models, relapse, Chemotherapy, Framingham Risk Score, business.industry, Hazard ratio, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Hodgkin Disease, Survival Analysis, Chemotherapy regimen, 3. Good health, Surgery, Transplantation, 030220 oncology & carcinogenesis, Female, prognosis, business, Hodgkin lymphoma, 030215 immunology
Abstract

IF 11.855; International audience; Background:Novel agents are changing the treatment of relapsed or refractory Hodgkin lymphoma (HL). Nevertheless, high-dose chemotherapy and autologous stem-cell transplantation (ASCT) are considered standard of care in eligible patients. To identify patients who could benefit most from novel therapeutic approaches, we investigated a comprehensive set of risk factors (RFs) for survival after ASCT.Methods:In this multinational prognostic multivariable modeling study, 23 potential RFs were retrospectively evaluated in HL patients from nine prospective trials with multivariable Cox proportional hazards regression analyses (part I). The resulting prognostic score was then validated in an independent clinical sample (part II).Results:In part I, we identified 656 patients treated for relapsed/refractory HL between 1993 and 2013 with a median follow-up of 60 months after ASCT. The majority of potential RFs had significant impact on progression-free survival (PFS) with hazard ratios (HR) ranging from 1.39 to 2.22. The multivariable analysis identified stage IV disease, time to relapse ≤3 months, ECOG performance status ≥1, bulk ≥5 cm and inadequate response to salvage chemotherapy [

Published
2017
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11. Molecular characterization of sarcomatoid clear cell renal cell carcinoma unveils new candidate oncogenic drivers

Author

Nizar M. Tannir, Yiyu Dong, Ronan Flippot, Xiaoping Su, Morgan Rouprêt, Jose A. Karam, Paul Russo, Eva Compérat, Gabriel G. Malouf, James J. Hsieh, Satish K. Tickoo, Ying-Bei Chen, Renzo G. DiNatale, Hui Yao, A. Ari Hakimi, Roger Mouawad, Jean Philippe Spano, Roy Mano, Kyle A. Blum, David Khayat, Thai H. Ho, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Strasbourg, Institut de Cancérologie de Strasbourg Europe (ICANS), Memorial Sloan Kettering Cancer Center (MSKCC), The University of Texas M.D. Anderson Cancer Center [Houston], CHU Tenon [AP-HP], Sorbonne Université (SU), Epidémiologie, Systèmes d'Information, Modélisation, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), MD Anderson Cancer Center [Houston], The University of Texas Health Science Center at Houston (UTHealth), Mayo Clinic [Scottsdale], Mayo Clinic, Mayo Clinic [Rochester], Washington University in Saint Louis (WUSTL), and univOAK, Archive ouverte

Subjects
Male, Cell, Gene regulatory network, lcsh:Medicine, Mice, 0302 clinical medicine, Gene Regulatory Networks, lcsh:Science, Cancer genetics, Cancer, Laser capture microdissection, YAP1, Neurofibromin 2, 0303 health sciences, Multidisciplinary, Kidney Neoplasms, Up-Regulation, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Signal Transduction, animal structures, [SDV.CAN]Life Sciences [q-bio]/Cancer, Laser Capture Microdissection, Protein Serine-Threonine Kinases, Biology, Article, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Carcinoma, Animals, Humans, Genetic Predisposition to Disease, Hippo Signaling Pathway, Carcinoma, Renal Cell, Adaptor Proteins, Signal Transducing, Cell Proliferation, 030304 developmental biology, Cell Nucleus, Hippo signaling pathway, Cell growth, lcsh:R, YAP-Signaling Proteins, Sequence Analysis, DNA, medicine.disease, Clear cell renal cell carcinoma, Transcriptional Coactivator with PDZ-Binding Motif Proteins, Mutation, Trans-Activators, Cancer research, lcsh:Q, Neoplasm Transplantation, Transcription Factors
Abstract

Sarcomatoid clear-cell renal cell carcinomas (sRCC) are associated with dismal prognosis. Genomic alterations associated with sarcomatoid dedifferentiation are poorly characterized. We sought to define the genomic landscape of sRCC and uncover potentially actionable therapeutic targets. We assessed the genomic landscape of sRCC using targeted panel sequencing including patients with microdissected sarcomatoid and epithelial components. Along with common genomic alterations associated with clear-cell histology, we found that Hippo was one of the most frequently altered pathways in these tumours. Hippo alterations were differentially enriched in sRCC compared to non-sRCC. Functional analysis showed that Hippo members mutations were associated with higher nuclear accumulation of YAP/TAZ, core effectors of the Hippo pathway. In a NF2-mutant sRCC model, YAP1 knockdown and NF2 reconstitution suppressed cell proliferation, tumour growth and invasion, both in vitro and in vivo. Overall, we show that Hippo pathway alterations are a feature of sRCC, and enable the exploration of the Hippo pathway as a novel potential therapeutic target.

Published
2020
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12. Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: a position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society

Author

Lyon, Alexander R., Dent, Susan, Stanway, Susanna, Earl, Helena, Brezden‐Masley, Christine, Cohen‐Solal, Alain, Tocchetti, Carlo G., Moslehi, Javid, Groarke, John D., Bergler‐Klein, Jutta, Khoo, Vincent, Tan, Li Ling, Anker, Markus S., Haehling, Stephan, Maack, Christoph, Pudil, Radek, Barac, Ana, Thavendirnathan, Paaladinesh, Ky, Bonnie, Neilan, Tomas G., Belenkov, Yury, Rosen, Stuart D., Iakobishvili, Zaza, Sverdlov, Aaron L., Hajjar, Ludhmila A., Macedo, Ariane V. S., Manisty, Charlotte, Ciardiello, Fortunato, Farmakis, Dimitrios, De Boer, Rudolf A., Skouri, Hadi, Suter, Thomas M., Cardinale, Daniela, Witteles, Ronald M., Fradley, Michael G., Herrmann, Joerg, Cornell, Robert F., Wechelaker, Ashutosh, Mauro, Michael J., Milojkovic, Dragana, Lavallade, Hugues, Ruschitzka, Frank, Coats, Andrew J. S., Seferovic, Petar M., Chioncel, Ovidiu, Thum, Thomas, Bauersachs, Johann, Andres, M. Sol, Wright, David J., López‐Fernández, Teresa, Plummer, Chris, Lenihan, Daniel, Imperial College London, Duke University [Durham], The Royal Marsden, University of Cambridge [UK] (CAM), Mount Sinai Hospital [Toronto, Canada] (MSH), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Naples Federico II = Università degli studi di Napoli Federico II, Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Medizinische Universität Wien = Medical University of Vienna, Monash University [Melbourne], Shanghai Center for Plant Stress Biology [CAS] (PSC), Chinese Academy of Sciences [Beijing] (CAS), German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Georg-August-University = Georg-August-Universität Göttingen, Hannover Medical School [Hannover] (MHH), Charles University [Prague] (CU), Georgetown University [Washington] (GU), University Health Network, University of Toronto, University of Pennsylvania, Massachusetts General Hospital [Boston], Sechenov First Moscow State Medical University, University College of London [London] (UCL), Tel Aviv University (TAU), University of Newcastle [Australia] (UoN), Universidade de São Paulo = University of São Paulo (USP), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, University of Cyprus [Nicosia] (UCY), University Medical Center Groningen [Groningen] (UMCG), American University of Beirut Faculty of Medicine and Medical Center (AUB), University of Bern, IRCCS Ospedale San Raffaele [Milan, Italy], Stanford University, Mayo Clinic [Rochester], Memorial Sloan Kettering Cancer Center (MSKCC), Hammersmith Hospital NHS Imperial College Healthcare, King's College Hospital (KCH), University hospital of Zurich [Zurich], University of Warwick [Coventry], Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), University of Belgrade [Belgrade], Emergency Institute for Cardiovascular Diseases 'Prof. Dr. C.C. Iliescu' [Bucharest, Romania], University of Medicine and Pharmacy 'Carol Davila' Bucharest (UMPCD), Royal Brompton Hospital, Liverpool Heart and Chest Hospital NHS Trust [UK] (LH&CH), La Paz University Hospital, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), leboeuf, Christophe, Lyon, Alexander R, Dent, Susan, Stanway, Susanna, Earl, Helena, Brezden-Masley, Christine, Cohen-Solal, Alain, Tocchetti, Carlo G, Moslehi, Javid, Groarke, John D, Bergler-Klein, Jutta, Khoo, Vincent, Tan, Li Ling, Anker, Markus S, von Haehling, Stephan, Maack, Christoph, Pudil, Radek, Barac, Ana, Thavendirnathan, Paaladinesh, Ky, Bonnie, Neilan, Tomas G, Belenkov, Yury, Rosen, Stuart D, Iakobishvili, Zaza, Sverdlov, Aaron L, Hajjar, Ludhmila A, Macedo, Ariane V S, Manisty, Charlotte, Ciardiello, Fortunato, Farmakis, Dimitrio, De Boer, Rudolf A, Skouri, Hadi, Suter, Thomas M, Cardinale, Daniela, Witteles, Ronald M, Fradley, Michael G, Herrmann, Joerg, Cornell, Robert F, Wechelaker, Ashutosh, Mauro, Michael J, Milojkovic, Dragana, de Lavallade, Hugue, Ruschitzka, Frank, Coats, Andrew J S, Seferovic, Petar M, Chioncel, Ovidiu, Thum, Thoma, Bauersachs, Johann, Andres, M Sol, Wright, David J, López-Fernández, Teresa, Plummer, Chri, Lenihan, Daniel, Lyon, Alexander R., Brezden‐masley, Christine, Cohen‐solal, Alain, Tocchetti, Carlo G., Groarke, John D., Bergler‐klein, Jutta, Anker, Markus S., Haehling, Stephan, Neilan, Tomas G., Rosen, Stuart D., Sverdlov, Aaron L., Hajjar, Ludhmila A., Macedo, Ariane V. S., De Boer, Rudolf A., Suter, Thomas M., Witteles, Ronald M., Fradley, Michael G., Cornell, Robert F., Mauro, Michael J., Lavallade, Hugue, Coats, Andrew J. S., Seferovic, Petar M., Andres, M. Sol, Wright, David J., and López‐fernández, Teresa

Subjects
Male, Heart failure, Androgen Antagonists, Antineoplastic Agents, Middle Aged, Risk Assessment, Cardiotoxicity, Risk prediction, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardio-oncology, risk factor, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cardiovascular Diseases, Heart Disease Risk Factors, Risk Factors, Neoplasms, Humans, Female, Aged
Abstract

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for CML targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies. This article is protected by copyright. All rights reserved.

Published
2020
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13. The C-terminal Domain of piggyBac Transposase Is Not Required for DNA Transposition

Author

Yan Jaszczyszyn, Yves Bigot, Peter Arensburger, Linda Beauclair, Nicolas Buisine, Thierry Lecomte, Florian Guillou, Laura Helou, Hugues Dardente, Alex Kentsis, Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), California State Polytechnic University [Pomona] (CAL POLY POMONA), Physiologie moléculaire et adaptation (PhyMA), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours (UT), Memorial Sloan Kettering Cancer Center (MSKCC), Cornell University [New York], Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut Français du Cheval et de l'Equitation [Saumur]-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
Gene isoform, Transposable element, transposon, Transposases, Nerve Tissue Proteins, Biology, Article, Chromosomes, Insert (molecular biology), Transposition (music), Mice, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Structural Biology, vertebrate, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology, Peptide sequence, Gene, ComputingMilieux_MISCELLANEOUS, Transposase, 030304 developmental biology, Recombination, Genetic, Genetics, DNA cleavage, 0303 health sciences, insertion preference, neuron, Transposase activity, DNA Transposable Elements, 030217 neurology & neurosurgery, HeLa Cells
Abstract

International audience; PiggyBac(PB)-like elements (pble) are members of a eukaryotic DNA transposon family. This family is of interest to evolutionary genomics because pble transposases have been domesticated at least 9 times in vertebrates. The amino acid sequence of pble transposases can be split into three regions: an acidic N-terminal domain (similar to 100 aa), a central domain (similar to 400 aa) containing a DD[D/E] catalytic triad, and a cysteine-rich domain (CRD; similar to 90 aa). Two recent reports suggested that a functional CRD is required for pble transposase activity. Here we found that two CRD-deficient pble transposases, a PB variant and an isoform encoded by the domesticated PB-derived vertebrate transposase gene 5 (pgbd5) trigger transposition of the Ifp2 pble. When overexpressed in HeLa cells, these CRD-deficient transposases can insert Ifp2 elements with proper and improper transposon ends, associated with deleterious effects on cells. Finally, we found that mouse CRD-deficient transposase Pgbd5, as well as PB, do not insert pbles at random into chromosomes. Transposition events occurred more often in genic regions, in the neighbourhood of the transcription start sites and were often found in genes predominantly expressed in the human central nervous system.

Published
2021
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14. The multidisciplinary management of gastro-oesophageal junction tumours: European Society of Digestive Oncology (ESDO): Expert discussion and report from the 16th ESMO World Congress on Gastrointestinal Cancer, Barcelona

Author

Van Laethem, J.-L., Carneiro, F., Ducreux, M., Messman, H., Lordick, F., Ilson, D.H., Allum, W., Haustermans, K, Lepage, C., Matysiak-Budnik, T., Cats, A, Schmiegel, W, Cervantes, A, Van Cutsem, E, Rougier, Ph, Seufferlein, Th, Service de Gastro-Entérologie, d'Hépato-Pancréatologie et d'Oncologie Digestive - Endoscopie Digestive (hôpital Erasme), Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Medical Fa, Oncologie digestive, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Institut Gustave Roussy (IGR), Department of Internal Medicine (Klinikum Augsburg), Klinikum Augsburg, Universität Leipzig [Leipzig], Memorial Sloane Kettering Cancer Center [New York], Royal Marsden Hospital NHS Foundation Trust, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Service d'hépato-gastro-entérologie, cancérologie digestive et assistance nutritionnelle [CHU de Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Netherlands Cancer Institute (NKI), Antoni van Leeuwenhoek Hospital, Medizinische Universitätsklinik, Ruhr-Universität Bochum [Bochum], Abtlg. Gastroenterologie und Hepatologie, INCLIVA, Universitat de València (UV), Université Paris Descartes - Paris 5 (UPD5), Universität Ulm - Ulm University [Ulm, Allemagne], Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Université Libre de Bruxelles [Bruxelles] ( ULB ) -Hôpital Erasme (Bruxelles), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Institut Gustave Roussy ( IGR ), Memorial Sloan Kettering Cancer Center ( MSKCC ), Katholieke Universiteit Leuven ( KU Leuven ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Netherlands Cancer Institute ( NKI ), Universitat de València ( UV ), Université Paris Descartes - Paris 5 ( UPD5 ), Ulm University, Université libre de Bruxelles (ULB)-Hôpital Erasme [Bruxelles] (ULB), and Université libre de Bruxelles (ULB)

Subjects
Esophageal Neoplasms, Esophageal Cancer, Adenocarcinoma, Clinical-Trial, Phase-Iii Trial, Medical Oncology, World Health Organization, Endoscopy, Gastrointestinal, Drug Therapy, Gastrectomy, Stomach Neoplasms, Perioperative Chemotherapy, Humans, Societies, Medical, Neoplasm Staging, Randomized Controlled Trials as Topic, Radiofrequency Ablation, Evidence-Based Medicine, Nutritional Support, Palliative Care, Endoscopic treatment, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Congresses as Topic, Term Survival Differences, Advanced Gastric-Cancer, Spain, Advanced Esophagogastric Cancer, Practice Guidelines as Topic, Gastro-oesophageal junction cancer, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Endoscopic Submucosal Dissection, Esophagogastric Junction, Resectable Esophageal, Esophagostomy, Multimodal therapy
Abstract

IF 2.719; International audience; The management of GOJ cancers remains controversial and may vary between countries. Evidence-based attitudes and guidelines are not easy to elaborate since most of the trials and studies reported mixed cases of oesophageal (both adenocarcinoma and squamous cell tumours), GOJ and gastric cancers. The aim of this expert discussion and position paper is to elaborate practical recommendations that integrate evidence-reported literature and experience-based attitude covering all clinical aspects of GOJ cancer across different specialities and countries in Europe.Opinion leaders, selected on scientific merit were asked to answer to a prepared set of questions covering the approach of GOJ tumours from definition to therapeutic strategies. All answers were then discussed during a plenary session and reported here in providing a well-balanced reflection of both clinical expertise and updated evidence-based medicine.Definition, classification, diagnosis and staging of GOJ tumours were updated and debated. Therapeutic aspects including endoscopic therapy, surgical management, both multimodal curative and palliative management were also reviewed for proposing practical and consensual positions and recommendations whenever possible.GOJ tumours deserve specific attention,not only for uniformising clinical management across countries but also for performing specific clinical and translational research,mainly in the curative perioperative setting.

Published
2016
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15. Proportions of blood-borne Vd1þ and Vd2þ T-cells are associated with overall survival of melanoma patients treated with ipilimumab

Author

Kilian Wistuba-Hamprecht, Marnix H Geukes Foppen, Bastian Schilling, Karin Haehnel, Jedd D. Wolchok, Emanuela Romano, Elisabeth Steinhagen-Thiessen, Alexander Martens, Mariaelena Capone, Phillip Wong, Dirk Schadendorf, Jianda Yuan, Amir Khammari, Ilja Demuth, Brigitte Dréno, Claus Garbe, Graham Pawelec, Christian U. Blank, Michael A. Postow, Benjamin Weide, Paolo A. Ascierto, Anis Larbi, Department of Internal Medicine II, Eberhard Karls Universität Tübingen-Center for Medical Research, University of Tübingen, The Netherlands Cancer Institute, Memorial Sloan Kettering Cancer Center ( MSKCC ), Weill Medical College of Cornell University [New York], Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Service de dermatologie [Nantes], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Istituto Nazionale Tumori IRCCS, Charité University Medical Center, Institute of Human Genetics, Singapore Immunology Network ( SIgN ), Agency for Science Technology and Research, German Cancer Consortium, Department of Dermatology, University Hospital Essen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen-Center for Medical Research, Memorial Sloane Kettering Cancer Center [New York], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), and Bernardo, Elizabeth

Subjects
Oncology, Male, Cancer Research, Cellular differentiation, medicine.medical_treatment, Medizin, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, T-Lymphocyte Subsets, Medicine, Cytotoxic T cell, Melanoma, Aged, 80 and over, medicine.diagnostic_test, Antibodies, Monoclonal, Cell Differentiation, Receptors, Antigen, T-Cell, gamma-delta, Middle Aged, Flow Cytometry, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, Immunotherapy, medicine.drug, Adult, medicine.medical_specialty, Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Article, Flow cytometry, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Biomarkers, Tumor, Humans, Aged, business.industry, Case-control study, medicine.disease, Case-Control Studies, Immunology, business, 030215 immunology
Abstract

International audience; Human γδ T-cells possess regulatory and cytotoxic capabilities, and could potentially influence the efficacy of immunotherapies. We analysed the frequencies of peripheral γδ T-cells, including their most prominent subsets (Vδ1+ and Vδ2+ cells) and differentiation states in 109 melanoma patients and 109 healthy controls. We additionally analysed the impact of γδ T-cells on overall survival (OS) calculated from the first dose of ipilimumab in melanoma patients. Higher median frequencies of Vδ1+ cells and lower median frequencies of Vδ2+ cells were identified in patients compared to healthy subjects (Vδ1+: 30% versus 15%, Vδ2+: 39% versus 64%, both p < 0.001). Patients with higher frequencies of Vδ1+ cells (≥30%) had poorer OS (p = 0.043) and a Vδ1+ differentiation signature dominated by late-differentiated phenotypes. In contrast, higher frequencies of Vδ2+ cells (≥39%) were associated with longer survival (p = 0.031) independent of the M category or lactate dehydrogenase level. Patients with decreasing frequencies of Vδ2+ cells under ipilimumab treatment had worse OS and a lower rate of clinical benefit than patients without such decreases. Therefore, we suggest frequencies of both Vδ1+ and Vδ2+ cells as candidate biomarkers for outcome in melanoma patients following ipilimumab. Further studies are needed to validate these results and to clarify whether they represent prognostic associations or whether γδ T-cells are specifically and/or functionally linked to the mode of action of ipilimumab.

Published
2016
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16. Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab

Author

Phillip Wong, Dirk Schadendorf, Christian U. Blank, Antje Sucker, Bastian Schilling, Thomas Eigentler, Jianda Yuan, Emanuela Romano, Alexander Martens, Marnix H Geukes Foppen, Kilian Wistuba-Hamprecht, Mariaelena Capone, Jedd D. Wolchok, Graham Pawelec, Brigitte Dréno, Claus Garbe, Amir Khammari, Peter Martus, Anna Maria Di Giacomo, Jessica C. Hassel, Michael A. Postow, Paolo A. Ascierto, Benjamin Weide, Michele Maio, Department of Internal Medicine II, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen-Center for Medical Research, University of Tübingen, Department of Dermatology [Tubingen, Germany], Tübingen University Hospital [Germany], The Netherlands Cancer Institute, Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Dermatology, University Hospital Essen, Fondazione IRCCS Istituto Nazionale dei Tumori, Division of Medical Oncology and Immunotherapy, University Hospital of Siena, German Cancer Consortium, Heidelberg University Hospital [Heidelberg], Department of Immunology [Tübingen, Germany], Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Bernardo, Elizabeth, University of Tübingen [Germany], Eberhard Karls Universität Tübingen-Center for Medical Research, Memorial Sloan Kettering Cancer Center ( MSKCC ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), and CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes )

Subjects
Male, Oncology, Cancer Research, medicine.medical_specialty, Skin Neoplasms, Lymphocyte, Medizin, Ipilimumab, [SDV.CAN]Life Sciences [q-bio]/Cancer, T-Lymphocytes, Regulatory, Article, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Biomarkers, Tumor, medicine, Humans, Lymphocyte Count, IL-2 receptor, Adverse effect, Melanoma, Aged, L-Lactate Dehydrogenase, Proportional hazards model, business.industry, Myeloid-Derived Suppressor Cells, FOXP3, Cancer, medicine.disease, 3. Good health, Treatment Outcome, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, Erythrocyte Count, Biomarker (medicine), Female, business, 030215 immunology, medicine.drug
Abstract

Purpose: To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Experimental Design: Frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan–Meier and Cox regression analysis, including calibration and discrimination by C-statistics. Results: Low baseline LDH, absolute monocyte counts (AMC), Lin−CD14+HLA-DR−/low-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+CD25+FoxP3+-Treg frequencies were significantly associated with better survival, and were considered in a combination model. Patients (43.5%) presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2–0) was also associated with OS (P < 0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort. Conclusions: A baseline signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12); 2908–18. ©2016 AACR.

Published
2016
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17. Classification of current anticancer immunotherapies

Author

Chiara Castelli, Axel Hoos, Anna Karolina Palucka, Aitziber Buqué, Kenneth J. Pienta, Aled Clayton, Daniel E. Speiser, Jean-Pierre Mach, Klas Kärre, Richard G. Vile, Maha Ayyoub, Norma Bloy, Theresa L. Whiteside, Eli Gilboa, Naiyer A. Rizvi, Cornelis J. M. Melief, Alexander Knuth, Bruno Silva-Santos, Lisa M. Coussens, James E. Talmadge, Jean-Yves Blay, Rolf Kiessling, Lorenzo Moretta, Alexander M.M. Eggermont, Estaban Celis, Anne Caignard, Mario P. Colombo, Abhishek D. Garg, José Manuel Bravo-San Pedro, Pramod K. Srivastava, Dmitry I. Gabrilovich, Wolf H. Fridman, Catherine Sautès-Fridman, Eric Tartour, Fabrizio Mattei, Patrizia Agostinis, Philipp Beckhove, Laura Bracci, Vincenzo Cerundolo, Giuseppe Giaccone, Fernando Aranda, Angel Porgador, Elisa E. Baracco, Radek Spisek, Jean Pierre Abastado, Michael T. Lotze, Ron N. Apte, Federica Cavallo, Benoît Van den Eynde, Weiping Zou, François Ghiringhelli, Hans Schreiber, Jitka Fucikova, Lorenzo Galluzzi, Adekunke Odunsi, Erika Vacchelli, Roland S. Liblau, Hideho Okada, Hiroshi Shiku, Laurence Zitvogel, Pawel Kalinski, Guido Kroemer, Oliver Kepp, George C. Prendergast, Eva Klein, Francesca Castoldi, Enrico Lugli, Jedd D. Wolchok, Anne Hosmalin, Sjoerd H. van der Burg, Hermann Wagner, Mark J. Smyth, Nicholas P. Restifo, Dirk Jäger, John M. Kirkwood, Gabriel A. Rabinovich, Sacha Gnjatic, Madhav V. Dhodapkar, E. A. Mittendorf, Douglas T. Fearon, Ignacio Melero, Marcus E. Peter, Jérôme Galon, Domenico Mavilio, Laura Senovilla, Claire E. Lewis, Barbara Seliger, Jeffrey S. Weber, UCL - SSS/DDUV - Institut de Duve, Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Paris-Sud - Paris 11 (UP11), Sotio a.c., Pole d’innovation thérapeutique en oncologie, Institut de Recherches Internationales Servier, Cell Death Research and Therapy (CDRT) Laboratory, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Group of Immune receptors of the Innate and Adaptive System, Institut d’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Cancer Vaccines and Immune Regulation, Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM), Translational Immunology Division, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità (ISS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unit of Immunotherapy of Human Tumors, Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], Molecular Biotechnology Center, Dept. of Molecular Biotechnology and Health Sciences, Università degli studi di Torino = University of Turin (UNITO), Cancer Immunology, Inflammation and Tolerance Program, Augusta University, University System of Georgia (USG)-University System of Georgia (USG), MRC Human Immunology Unit, The Weatherall Institute of Molecular Medicine, University of Oxford-University of Oxford, Department of Oncology - Pathology, Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm]-Karolinska Institutet [Stockholm], Institute of Cancer & Genetics, Cardiff University, Velindre Cancer Centre, Knight Cancer Institute, Oregon Health and Science University [Portland] (OHSU), Sect. of Hematology and Immunobiology,Yale Cancer Center, Yale University [New Haven], Institut Gustave Roussy (IGR), Cold Spring Harbor Laboratory, NY, Cold Spring Harbor, Centre de Recherche des Cordeliers (CRC), Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University [Prague] (CU), Dept. of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Lombardi Comprehensive Cancer Center, Georgetown University [Washington] (GU), Dept. of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami [Coral Gables], Glaxo Smith Kline, Cancer Immunotherapy Consortium, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Center for Tumor Diseases, University Medical Center Heidelberg, Hillman Cancer Center, University of Pittsburg, Department of Surgery, Cancer Institute-University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Dept. of Immunology and Infectious Diseases and Microbiology, University of Pittsburgh (PITT), Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institutet [Stockholm], Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Dept. of Oncology, Karolinska Institute Hospital, Cancer Institute Laboratory, Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Institut de Biochimie, Université de Lausanne = University of Lausanne (UNIL), Dept. of Medical Biotechnologies and Translational Medicine, Università degli Studi di Milano = University of Milan (UNIMI), Dept. of Immunology, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Clínica Universidad de Navarra [Pamplona], ISA Therapeutics, Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Research Dept. of Surgical Oncology, The University of Texas, Istituto Giannina Gaslini, Center for Immunotherapy [Buffalo], Roswell Park Cancer Institute [Buffalo] (RPCI), Dept. of Neurological Surgery, University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), The Jackson Laboratory [Bar Harbor] (JAX), Div. of Hematology/Oncology, Northwestern University, The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev (BGU)-Faculty of Health Sciences and Cancer Research Center, Cell Biology and Signaling Program, Thomas Jefferson University-Sidney Kimmel Cancer Center, Jefferson (Philadelphia University + Thomas Jefferson University)-Jefferson (Philadelphia University + Thomas Jefferson University), Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental [Buenos Aires] (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET)-Consejo Nacional de Investigaciones Científicas y Técnicas [Buenos Aires] (CONICET), Memorial Sloane Kettering Cancer Center [New York], Dept. of Pathology, The Cancer Research Center, University of Chicago, Institute of Medical Immunology, Martin-Luther-Universität Halle Wittenberg (MLU), Department of Immuno-gene Therapy, Mie University, Instituto de Medicina Molecular, Universidade de Lisboa = University of Lisbon (ULISBOA), Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, School of Medicine, University of Queensland [Brisbane], Ludwig Cancer Research Center, Dept. of Immunology, University of Connecticut (UCONN), Carole and Ray Neag Comprehensive Cancer Center, Laboratory of Transplantation Immunology, Dept. of Pathology and Microbiology, University of Nebraska Medical Center, University of Nebraska System-University of Nebraska System, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), 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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immunologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Dept. of Clinical Oncology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Ludwig Institute for Cancer Research, de Duve Institute, Dept. of Molecular Medicine and Immunology, Mayo Clinic College of Medicine, Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Donald A. Adam Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center & Research Institute, University of Pittsburgh School of Medicine, Dept. of Medicine and Ludwig Center, Weill Medical College of Cornell University [New York], Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Pôle de biologie, GK is supported by the Ligue contre le Cancer(équipe labelisée), Agence Nationale de la Recherche(ANR), Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, Institut National du Cancer(INCa), Fondation Bettencourt-Schueller, Fondation deFrance, Fondation pour la Recherche Médicale (FRM), theEuropean Commission (ArtForce), the European ResearchCouncil (ERC), the LabEx Immuno-Oncology, the SIRICStratified Oncology Cell DNA Repair and Tumor ImmuneElimination (SOCRATE), the SIRIC Cancer Researchand Personalized Medicine (CARPEM), and the ParisAlliance of Cancer Research Institutes (PACRI). MPC issupported by Association for Cancer Research (AIRC). SGis supported by Cancer Vaccine Collaborative and CancerResearch Institute. MJS is supported by the NationalHealth and Medical Research Council of Australia, the QIMR Berghofer Medical Research Institute, andthe Susan G Komen Breast Cancer Foundation. FM issupported by a grant from the Italian Ministry of Health., Repositório da Universidade de Lisboa, Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto Superiore di Sanità, Università degli studi di Torino (UNITO), University of Oxford [Oxford]-University of Oxford [Oxford], University of Pennsylvania [Philadelphia], Georgetown University, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne (UNIL), University of Milan, Roswell Park Cancer Institute [Buffalo], University of California [San Francisco] (UCSF), University of California-University of California, Universidade de Lisboa (ULISBOA), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Bos, Mireille, Apoptose, cancer et immunité ( Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138 ), Institut Gustave Roussy ( IGR ) -Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris-Sud - Paris 11 ( UP11 ), Catholic University of Leuven ( KU Leuven ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), German Cancer Research Center, Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Università degli studi di Torino ( UNITO ), Georgia Regents University Cancer Center, Cancer Center Karolinska [Karolinska Institutet] ( CCK ), Oregon Health & Science University [Portland] ( OHSU ), Institut Gustave Roussy ( IGR ), Centre de Recherche des Cordeliers ( CRC ), Université Paris Diderot - Paris 7 ( UPD7 ) -École pratique des hautes études ( EPHE ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Charles University, Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), University of Miami, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Cancer Institute-University of Pittsburgh, University of Pittsburgh, Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Centre de Physiopathologie de Toulouse Purpan ( CPTP ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lausanne ( UNIL ), Center for Immunotherapy, University of California [San Francisco] ( UCSF ), The Jackson Laboratory for Genomics Medicine, Ben-Gurion University of the Negev ( BGU ) -Faculty of Health Sciences and Cancer Research Center, Instituto de Biología y Medicina Experimental (IBYME), National Cancer Institute (NCI), Memorial Sloan Kettering Cancer Center ( MSKCC ), Martin Luther University Halle-Wittenberg, Mie University Graduate School of Medicine, Universidade de Lisboa ( ULISBOA ), University of Lausanne, University of Connecticut School of Medicine, Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Université Catholique de Louvain ( UCL ), Technical University of Munich ( TUM ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), and Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
immunostimulatory cytokines, medicine.medical_treatment, Review, Bioinformatics, DNA-based vaccines, Efficacy, 0302 clinical medicine, Cancer immunotherapy, Neoplasms, peptide-based vaccines, 0303 health sciences, Patología, purl.org/becyt/ford/3.1 [https], CANCER, 3. Good health, Medicina Básica, Oncology, checkpoint blockers, 030220 oncology & carcinogenesis, QR180, purl.org/becyt/ford/3 [https], Immunotherapy, CIENCIAS MÉDICAS Y DE LA SALUD, medicine.drug_class, Inmunología, adoptive cell transfer, dendritic cell-based interventions, oncolytic viruses, Toll-like receptor agonists, Monoclonal antibody, RC0254, 03 medical and health sciences, Immune system, Antigen, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, IMMUNOTHERAPIES, business.industry, Cancer, medicine.disease, R1, Oncolytic virus, Immunology, business
Abstract

© 2014. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited., During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

Published
2014

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