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19 results on '"Istituto Nazionale Tumori-IRCCS Foundation"'

1. Safety and immunogenicity of the PRAME cancer immunotherapeutic in metastatic melanoma: results of a phase I dose escalation study

Author

P.A. Ascierto, Jamila Louahed, Ralf Gutzmer, Dirk Schadendorf, Lev V. Demidov, Armando Santoro, N. Vanhoutte, Jochen Utikal, Carmen Loquai, P M De Sousa Alves, Paola Queirolo, Frederic Lehmann, Axel Hauschild, B. Dréno, V G Brichard, Marc Gillet, Erwin S. Schultz, B. Salaun, Jean-Jacques Grob, Licia Rivoltini, Thierry Lesimple, Silvija Jarnjak, Ruggero Ridolfi, Alberto Testori, Evgeny Levchenko, Skin Cancer Center Hannover, Hannover Medical School [Hannover] (MHH), Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori-IRCCS Foundation, Petrov Research Insitut of Oncology, Division of Melanoma and Muscolocutaneous sarcoma, European Institute of Oncology, Skin Cancer Unit of the German Cancer Research Center Heidelberg, University Mannheim, Istituto Nazionale per lo studio e la cura dei Tumori, Naples, Italy, Cancer Research Center, Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Immunoterapia e Terapia Cellulare Somatica, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Department of Dermatology, University Hospital Essen, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Johannes Gutenberg - Universität Mainz (JGU), 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), Schleswig-Holstein University Hospitals, Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Surgical oncology Centre Eugènes Marquis, Centre Eugènes Marquis, GSK Vaccines - Belgium, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Bernardo, Elizabeth, and Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS

Subjects
safety, Cancer Research, medicine.drug_class, medicine.medical_treatment, Medizin, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, immunogenicity, Immunostimulant, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer immunotherapy, medicine, 030304 developmental biology, Original Research, PRAME antigen, 0303 health sciences, PRAME, cancer immunotherapy, business.industry, Melanoma, Immunogenicity, Cancer, medicine.disease, 3. Good health, Oncology, 030220 oncology & carcinogenesis, Immunology, Chills, medicine.symptom, business, metastatic melanoma
Abstract

Purpose The PRAME tumour antigen is expressed in several tumour types but in few normal adult tissues. A dose-escalation phase I/II study (NCT01149343) assessed the safety, immunogenicity and clinical activity of the PRAME immunotherapeutic (recombinant PRAME protein (recPRAME) with the AS15 immunostimulant) in patients with advanced melanoma. Here, we report the phase I dose-escalation study segment. Patients and methods Patients with stage IV PRAME-positive melanoma were enrolled to 3 consecutive cohorts to receive up to 24 intramuscular injections of the PRAME immunotherapeutic. The RecPRAME dose was 20, 100 or 500 µg in cohorts 1, 2 and 3, respectively, with a fixed dose of AS15. Adverse events (AEs), including predefined dose-limiting toxicity (DLT) and the anti-PRAME humoral response (ELISA), were coprimary end points. Cellular immune responses were evaluated using in vitro assays. Results 66 patients were treated (20, 24 and 22 in the respective cohorts). AEs considered by the investigator to be causally related were mostly grade 1 or 2 injection site symptoms, fatigue, chills, fever and headache. Two DLTs (grade 3 brain oedema and proteinuria) were recorded in two patients in two cohorts (cohorts 2 and 3). All patients had detectable anti-PRAME antibodies after four immunisations. Percentages of patients with predefined PRAME-specific-CD4+T-cell responses after four immunisations were similar in each cohort. No CD8+ T-cell responses were detected. Conclusions The PRAME immunotherapeutic had an acceptable safety profile and induced similar anti-PRAME-specific humoral and cellular immune responses in all cohorts. As per protocol, the phase II study segment was initiated to further evaluate the 500 µg PRAME immunotherapeutic dose. Trial registration number NCT01149343, Results.

Published
2016
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2. Orexigenic neuropeptide 26RFa: new evidence for an adaptive profile of appetite regulation in anorexia nervosa

Author

Fauquembergue, Emilie, Toutirais, Olivier, Tougeron, David, Drouet, Aurélie, Le Gallo, Matthieu, Desille, Mireille, Cabillic, Florian, De La Pintière, Cécile Thomas, Iero, Manuela, Rivoltini, Licia, Baert-Desurmont, Stéphanie, Vaudry, Hubert, Sesboüe, Richard, Frebourg, Thierry, Latouche, Jean-Baptiste, Catros, Véronique, Gach, D, Belkacemi, D, Lefranc, R, Perlikowski, D, Masson, J., Walet-Balieu, R, Do-Rego, J., Galas, R, Schapman, D., Lamtahri, D, Tonon, D, Vaudry, D., Chuquet, J., Gach, K., Belkacemi, O., Lefranc, B., Perlikowski, P., Walet-Balieu, M.-L., Galas, L., Lamtahri, R., Tonon, M.-C., Galusca, Bogdan, Jeandel, Lydie, Germain, Natacha, Alexandre, David, Leprince, Jérôme, Anouar, Youssef, Estour, Bruno, Chartrel, Nicolas, Biothérapies Innovantes, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), CRLCC Eugène Marquis (CRLCC), Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori-IRCCS Foundation, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Différenciation et communication neuronale et neuroendocrine (DC2N), Endocrinologie, Centre Hospitalier Universitaire de Saint-Etienne, Université de Rennes - Faculté de Médecine (UR Médecine), Université de Rennes (UR), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)

Subjects
food intake, Anorexia Nervosa, Endocrinology, Diabetes and Metabolism, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Clinical Biochemistry, Appetite, diazepam-binding inhibitor, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, MESH: Neuropeptides, Biochemistry, 0302 clinical medicine, Endocrinology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Medicine, Bulimia, media_common, 2. Zero hunger, 0303 health sciences, digestive, oral, and skin physiology, MESH: Energy Metabolism, anxiety, Adaptation, Physiological, Ghrelin, Circadian Rhythm, Eating disorders, Anorexia nervosa (differential diagnoses), MESH: Young Adult, Female, medicine.symptom, MESH: Anorexia Nervosa, hormones, hormone substitutes, and hormone antagonists, MESH: Malnutrition, Binge-Eating Disorder, medicine.drug, Adult, medicine.medical_specialty, phosphorylated peptide, MESH: Rats, Adolescent, media_common.quotation_subject, MESH: Ghrelin, 030209 endocrinology & metabolism, Context (language use), 03 medical and health sciences, endozepines, Young Adult, MESH: Cross-Sectional Studies, Internal medicine, Orexigenic, Humans, Circadian rhythm, MESH: Bulimia, MESH: Circadian Rhythm, 030304 developmental biology, MESH: Adolescent, MESH: Humans, Binge eating, business.industry, Biochemistry (medical), Malnutrition, Neuropeptides, MESH: Adult, MESH: Binge-Eating Disorder, medicine.disease, MESH: Adaptation, Physiological, Cross-Sectional Studies, octadecaneuropeptide, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Appetite, business, Energy Metabolism, MESH: Female
Abstract

Restrictive anorexia nervosa (AN) presents an adaptive appetite regulating profile including mainly high levels of ghrelin. Because this adaptive mechanism is not effective on food intake, other appetite-regulating peptides need to be explored. 26RFa is a hypothalamic neuropeptide that stimulates appetite, gonadotropin release, and bone metabolism.The objective of the study was to evaluate the circadian levels of 26RFa in AN patients compared with healthy subjects, other eating disorders, and constitutional thinness (CT).This was a cross-sectional study performed in an endocrine unit and an academic laboratory.Five groups of age-matched young women were included in the study: 19 restrictive AN, 10 AN with bingeing/purging episodes, 14 with CT, 10 bulimic, and 10 normal-weight controls.Twelve-point circadian profiles of plasma 26RFa levels were measured in each subject.Significant circadian variations of 26 RFA were noticed in controls with higher values in the morning and abrupt decrease at noon. Twenty-four-hour mean 26RFa levels were significantly increased in restrictive AN and AN with bingeing/purging episodes (P0.001), predominantly in the afternoon and evening when compared with controls. Preprandial rises of 26 RFA were noticed in AN patients. Mean 26RFa levels trend to be higher in CT than in controls (P = 0.06) and significantly lower than in AN. The bulimic patients presented a circadian profile of 26RFa similar to that of controls.High levels of circulating 26RFa observed in AN patients might reflect an adaptive mechanism of the organism to promote energy intake and to increase fat stores in response to undernutrition.

Published
2012
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3. Future perspectives in melanoma research. Meeting report from the 'Melanoma Research: a bridge Naples-USA. Naples, December 6th-7th 2010'

Author

Mario Sznol, Licia Rivoltini, Nicola Mozzillo, Frederic Lehmann, Michele Maio, Alistair J. Cochran, Claudio Dansky Ullmann, Bernard A. Fox, Giuseppe Palmieri, Soldano Ferrone, Stefano Bertuzzi, Antoni Ribas, Eleonora De Maio, David F. Stroncek, John M. Kirkwood, Mohamed Kashani-sabet, Ruth Halaban, Mary J.C. Hendrix, F. M. Marincola, Keith T. Flaherty, Ena Wang, Douglas J Schwartzentruber, Jérôme Galon, Peter P. Lee, Paolo A. Ascierto, James Chih-Hsin Yang, Department of Melanoma, Sarcoma, and Head and Neck Disease, Instituto Nazionale Tumori Fondazione Pascale, Office of Science Policy Analysis, National Institutes of Health, Unit of Cancer Genetics, National Research Council (CNR)-Institute of Biomolecular Chemistry, Department of Dermatology, Yale University School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Infectious Diseases and Immunogenetics Section (IDIS), Department of Transfusion Medicine-Clinical Center and Center for Human Immunology (CHI), NIH, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori-IRCCS Foundation, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Laboratory of Molecular and Tumor Immunology, Providence Portland Medical Center-Robert W. Franz Cancer Research Center-Earle A. Chiles Research Institute, Department of Molecular Microbiology and Immunology, Oregon Health and Science University [Portland] (OHSU), Department of Medicine, Division of Hematology/Oncology-Pittsburgh Cancer Institute-University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Cancer Therapy Evaluation Program DCTD, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH)-Clinical Investigations Branch, Cancer Immunotherapeutics Business Unit, GlaxoSmithKline Biologicals, Yale Cancer Center, Center for Cancer Care, Indiana University System, Medical Oncology and Immunotherapy, Hospital of Siena-Department of Oncology-Instituto Toscano Tumori, Cancer Center, Massachusetts General Hospital [Boston], Centre de Recherche des Cordeliers (CRC (UMR_S 872)), 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)-Centre National de la Recherche Scientifique (CNRS), Jonsson Comprehensive Cancer Center, Surgical Brach, National Institute of the Health (NIH), This work was supported by the Italian Ministry of Health 'Progetto Ricerca Corrente Istituto Nazionale Tumori Pascale M2/11 Approccio multidisciplinare dalla ricerca alla cura del melanoma' and by Fondazione Melanoma Onlus., Yale School of Medicine [New Haven, Connecticut] (YSM), University of California (UC)-University of California (UC), Yale School of Medicine, University of Pittsburgh, Cancer Institute, Infectious Diseases and Immunogenetics Section ( IDIS ), David Geffen School of Medicine at UCLA, University of California at Los Angeles [Los Angeles] ( UCLA ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Oregon Health and Science University, Division of Hematology/Oncology-Pittsburgh Cancer Institute-University of Pittsburgh, National Cancer Institute ( NIH ) -Clinical Investigations Branch, Indiana University Health Goshen, Massachusetts General Hospital, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), and BMC, Ed.

Subjects
Pathology, medicine.medical_specialty, Library science, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, General Biochemistry, Genetics and Molecular Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Clinical investigation, International congress, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, melanoma, Medicine, 030304 developmental biology, Pharmaceutical industry, 0303 health sciences, Government, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Melanoma patient, business.industry, lcsh:R, General Medicine, 3. Good health, Clinical Practice, Clinical trial, 030220 oncology & carcinogenesis, Molecular targets, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Progress in understanding the molecular basis of melanoma has made possible the identification of molecular targets with important implications in clinical practice. In fact, new therapeutic approaches are emerging from basic science and it will be important to implement their rapid translation into clinical practice by active clinical investigation. The first meeting of Melanoma Research: a bridge Naples-USA, organized by Paolo A. Ascierto (INT, Naples, Italy) and Francesco Marincola (NIH, Bethesda, USA) took place in Naples, on 6-7 December 2010. This international congress gathered more than 30 international and Italian faculty members and was focused on recent advances in melanoma molecular biology, immunology and therapy, and created an interactive discussion across Institutions belonging to Government, Academy and Pharmaceutical Industry, in order to stimulate new approaches in basic, translational and clinical research. Four topics of discussion were identified: New pathways in Melanoma, Biomarkers, Clinical Trials and New Molecules and Strategies.

Published
2011
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4. Defining the critical hurdles in cancer immunotherapy

Author

Andrea Nicolini, Francesco M. Marincola, William E. Carson, Paolo A. Ascierto, Michele Maio, Jedd D. Wolchok, Michael T. Lotze, Jirina Bartunkova, Weihua Xiao, Hauke Winter, Barbara Seliger, Jon M. Wigginton, Cedrik M. Britten, Ignacio Melero, Guido Kroemer, Neil L. Berinstein, Jill O'Donnell-Tormey, Heinz Zwierzina, Lothar Bergmann, Lloyd J. Old, Christian H. Ottensmeier, Jérôme Galon, Per thor Straten, Koji Kawakami, Michael Papamichail, Yutaka Kawakami, Michael I. Nishimura, Mary L. Disis, Steinar Aamdal, C. J. M. Melief, Pedro Romero, Kristen Hege, Wenru Song, Pawel Kalinski, Jonathan L. Bramson, Harpreet Singh-Jasuja, Jens Peter Marschner, Bernard A. Fox, Samir N. Khleif, Brad H. Nelson, Marij J. P. Welters, Elizabeth M. Jaffee, Patrick Hwu, Rik J. Scheper, Robert C. Rees, Giuseppe Masucci, Hideaki Tahara, Cristina Bonorino, Glenn Dranoff, Ernest C. Borden, William J. Murphy, Zhigang Tian, Michael B. Atkins, Robert O. Dillman, Thomas F. Gajewski, Hiroshi Shiku, Leif Håkansson, Michael J. Mastrangelo, Lisa H. Butterfield, Shukui Qin, Laurence Zitvogel, Harry Dolstra, Michele Guida, George Coukos, Mohamed L. Salem, Xuetao Cao, Giorgio Parmiani, Enrico Proietti, Ena Wang, Sylvia Janetzki, A. Raja Choudhury, Gerd Ritter, Hyam I. Levitsky, Kunle Odunsi, Kohzoh Imai, Paul von Hoegen, Christoph Huber, Réjean Lapointe, Antoni Ribas, Dolores J. Schendel, Pamela S. Ohashi, Beatrix Kotlan, Cécile Gouttefangeas, James H. Finke, Alfred E. Chang, Howard L. Kaufman, Lindy G. Durrant, Sjoerd H. van der Burg, Jared Gollob, Dainius Characiejus, Tara Withington, Padmanee Sharma, Ronald B. Herberman, Cristina Maccalli, Ulrich Keilholtz, Axel Hoos, Graham Pawelec, Fabio Grizzi, Tanja D. de Gruijl, F. Stephen Hodi, Ruggero Ridolfi, James P. Allison, Licia Rivoltini, Carl H. June, Rolf Kiessling, Department of Molecular Microbiology and Immunology, Oregon Health and Science University [Portland] (OHSU)-Knight Cancer Institute, Earle A. Chiles Research Institute, Providence Portland Medical Center-Robert W. Franz Research Center-Providence Cancer Center, Clinical Cooperation Group 'Immune Monitoring', German Research Center for Environmental Health-Helmholtz Centre Munich-Institute of Molecular Immunology, Division of Hematology Oncology, University of Pittsburgh Cancer Institute-Departments of Medicine, Department of Surgery, Cancer Institute-University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Department of Immunology, University of Pittsburgh Cancer Institute, Department of Clinical Cancer Research, The Norwegian Radium Hospital-Oslo University Hospital [Oslo], Memorial Sloane Kettering Cancer Center [New York], Howard Hughes Medical Institute (HHMI), Medical Oncology and Innovative Therapy, Instituto Nazionale Tumori-Fondazione 'G. Pascale', Beth Israel Deaconess Medical Center, Harvard Medical School [Boston] (HMS), Institute of Immunology, Charles University [Prague] (CU)-FOCIS Center of Excellence-2nd Medical School, Goethe-Universität Frankfurt am Main, IRX Therapeutics, Stanford University-ImmunoVaccine Inc., Instituto Nacional para o Controle do Câncer, Instituto de Pesquisas Biomédicas-PUCRS Faculdade de Biociências, Department of Solid Tumor Oncology, Cleveland Clinic, Department of Translational Hematology and Oncology Research, Department of Pathology, McMaster University [Hamilton, Ontario], University Medical Center Mainz, III. Medical Department, Ribological GmbH, Department of Medicine-University Medical Center of the Johannes Gutenberg-University-Clinical Development, BioNTech AG, Chinese Academy of Medical Sciences, Second Military Medical University-National Key Laboratory of Medical Immunology, Ohio State University [Columbus] (OSU), University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Institute of Oncology, Vilnius University [Vilnius]-Faculty of Medicine, Department of Medicine, University of Queensland [Brisbane], Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], Department of Medical Oncology, VU Medical Center-Cancer Center Amsterdam, Hoag Institute for Research and Education, Hoag Cancer Institute, Department of Laboratory Medicine, Radboud university [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Nijmegen Medical Centre [Nijmegen], Brigham and Women's Hospital [Boston], Dana-Farber Cancer Institute [Boston], Academic Department of Clinical Oncology, University of Nottingham, UK (UON), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Alnylam Pharmaceuticals, Inc., Institute for Cell Biology, Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Oncology Department, University of Lund, CanImGuide Therapeutics AB, University of California [San Francisco] (UCSF), University of California, Intrexon Corporation, Germantown, Bristol-Myers Squibb Company, Translational Oncology & Immunology, Centre TRON at the Mainz University Medical Center, Department of Melanoma Medical Oncology, The University of Texas M.D. Anderson Cancer Center [Houston], The Institute of Medical Science, The University of Tokyo (UTokyo), Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine [Baltimore]-Johns Hopkins University School of Medicine [Baltimore], ZellNet Consulting, Pathology and Laboratory Medicine, University of Pennsylvania [Philadelphia], Rush University Cancer Center, Rush University Medical Center [Chicago], School of Medicine and Public Health, Kyoto University [Kyoto], Division of Cellular Signaling, Institute for Advanced Medical Research, Dept. of Hematology and Medical Oncology, Charité Comprehensive Cancer Center, Cancer Vaccine Section, NCI, Department of Oncology - Pathology, Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm]-Karolinska Institutet [Stockholm], Department of Molecular Immunology and Toxicology, Center of Surgical and Molecular Tumor pathology, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), School of Medicine, Johns Hopkins University (JHU)-Oncology Center, Department of Molecular Oncology, Foundation San Raffaele Scientific Institute, Medical Oncology and Immunotherapy, Istituto Toscano Tumori-University Hospital of Siena-Department of Oncology, Merck KGaA, Merck & Co. Inc, Thomas Jefferson University, Department of Oncology-Pathology, karolinska institute, CIMA, CUN and Medical School University of Navarra, Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Davis Medical Center, Sacramento-University of California, Deeley Research Centre, BC Cancer Agency (BCCRC), Department of Internal Medicine, University of Pisa - Università di Pisa, Oncology Institute, Loyola University Medical Center (LUMC)-Cardinal Bernardin Cancer Center, Tumor Immunology and Immunotherapy Program, Roswell Park Cancer Institute [Buffalo]-Department of Gynecologic Oncology, Ontario Cancer Institute, University Health Network, Cancer Immunotherapy Consortium (CIC), Cancer Research Institute, Cancer Research, Ludwig Institute, Experimental Cancer Medicine Centre, University of Southampton-Faculty of Medicine, Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Unit of Immuno-Biotherapy of Melanoma and Solid Tumors, San Raffaele Scientific Institute, Center for Medical Research, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanita', Chinese PLA Cancer Center, Department of Oncology-The Eighty-First Hospital, The John van Geest Cancer Research Centre, School of Science and Technology-Nottingham Trent University, Jonsson Comprehensive Cancer Center, Immunoterapia e Terapia Cellulare Somatica, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori-IRCCS Foundation, Division of Clinical Onco-Immunology, Université de Lausanne (UNIL)-Ludwig Center for Cancer Research, Immunology and Biotechnology Unit, Faculty of Science-Department of Zoology-Tanta University, VU University Medical Center [Amsterdam], Institute of Medical Immunology, Martin-Luther-Universität Halle Wittenberg (MLU), Departments of Immunology, Department of Cancer Vaccine, Mie University, Department of Immuno-gene Therapy, Immatics Biotechnologies GmbH, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen-Department of Immunology-Institute for Cell Biology, Millennium: The Takeda Oncology Company, Pfizer Oncology, Center for Cancer Immune Therapy (CCIT), Herlev and Gentofte Hospital-Department of Hematology, Department of Surgery and Bioengineering, The University of Tokyo (UTokyo)-Institute of Medical Science-Advanced Clinical Research Center, School of Life Sciences-University of Science & Technology of China [Suzhou], Institute of Immunopharmacology & Immunotherapy, Shandong University-School of Pharmaceutical Sciences, Experimental Cancer Immunology and Therapy, Leiden University Medical Center (LUMC)-Department of Clinical Oncology, Euraccine Consulting Group, Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine-Clinical Center-National Institute of Health NIH), Center for Human Immunology (CHI), National Institute of Health (NIH), Leiden University Medical Center (LUMC)-Department of Clinical Oncology (K1-P), Ludwig Maximilians University-Klinikum Grosshadern, Biological Therapy of Cancer, Medical and Surgical Services Organizations-International Society For Biological Therapy Of Cancer, School of Life Science-University of Science and Technology of China [Hefei] (USTC), Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Department Haematology and Oncology, Innsbruck Medical University [Austria] (IMU), Medical Center, University of Chicago, Discovery Medicine-Oncology, Tumor Vaccine Group, University of Washington [Seattle]-Center for Translational Medicine in Women's Health, The work of CIMT-CIP was supported by a grant from the Wallace Coulter foundation (Florida, USA)., Helmholtz Centre Munich-Institute of Molecular Immunology-Helmholtz Zentrum München = German Research Center for Environmental Health, University of Pennsylvania-University of Pennsylvania, Radboud University [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Nijmegen Medical Centre [Nijmegen], 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)-Centre National de la Recherche Scientifique (CNRS), Lund University [Lund], University of California [San Francisco] (UC San Francisco), University of California (UC), University of Pennsylvania, Kyoto University, Sacramento-University of California (UC), Université de Lausanne = University of Lausanne (UNIL)-Ludwig Center for Cancer Research, Klinikum Grosshadern-Ludwig-Maximilians University [Munich] (LMU), University of Science and Technology of China [Hefei] (USTC)-School of Life Science, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), BMC, Ed., Computer Systems, Medical oncology laboratory, Pathology, CCA - Immuno-pathogenesis, CCA - Innovative therapy, Oregon Health and Science University-Knight Cancer Institute, Cancer Institute-University of Pittsburgh, The Norwegian Radium Hospital-Oslo University Hospital, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, Howard Hughes Medical Institute, Ludwig Center for Cancer Immunotherapy, A Teaching Hospital of Harvard Medical School, Charles University [Prague]-FOCIS Center of Excellence-2nd Medical School, Stanford University [Stanford]-ImmunoVaccine Inc., Ohio State University [Columbus] ( OSU ), University of Michigan Medical Center, University of Pennsylvania Medical Center, Radboud university [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Nijmegen Medical Centre, University of Nottingham, UK ( UON ), Cleveland Clinic Foundation, Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), Istituto Clinico Humanitas [Milan] ( IRCCS Milan ), Humanitas University [Milan] ( Hunimed ), University of California [San Francisco] ( UCSF ), Harvard Medical School [Boston] ( HMS ), MD Anderson Cancer Center, The University of Tokyo, Rush University Medical Center, Cancer Center Karolinska [Karolinska Institutet] ( CCK ), Centre Hospitalier de l'Université de Montréal-Hôpital Notre-Dame Research Center ( CRCHUM ), Department of Medicine-University of Montreal, Johns Hopkins University ( JHU ) -Oncology Center, BC Cancer Agency ( BCCRC ), University of Pisa [Pisa], Loyola University Medical Center ( LUMC ) -Cardinal Bernardin Cancer Center, Cancer Immunotherapy Consortium ( CIC ), University of Southampton [Southampton]-Faculty of Medicine, Eberhard Karls Universität Tübingen, University of Lausanne-Ludwig Center for Cancer Research, Martin-Luther-University Halle-Wittenberg, Mie University Graduate School of Medicine, Eberhard Karls Universität Tübingen-Department of Immunology-Institute for Cell Biology, Center for Cancer Immune Therapy ( CCIT ), Herlev Hospital-Department of Hematology, The University of Tokyo-Institute of Medical Science-Advanced Clinical Research Center, Infectious Disease and Immunogenetics Section ( IDIS ), Center for Human Immunology ( CHI ), University of Science and Technology of China [Hefei] ( USTC ) -School of Life Science, 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 ), Innsbruck Medical University [Austria] ( IMU ), Department of Medicine-Clinical Development, BioNTech AG-Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Universiteit Leiden-Universiteit Leiden, Roswell Park Cancer Institute [Buffalo] (RPCI)-Department of Gynecologic Oncology, Istituto Superiore di Sanità (ISS), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Universiteit Leiden-Universiteit Leiden-Department of Clinical Oncology, and Universiteit Leiden-Universiteit Leiden-Department of Clinical Oncology (K1-P)

Subjects
medicine.medical_specialty, International Cooperation, medicine.medical_treatment, Alternative medicine, lcsh:Medicine, Translational research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cancer Immunotherapy, General Biochemistry, Genetics and Molecular Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Translational Research, Biomedical, 03 medical and health sciences, SDG 17 - Partnerships for the Goals, 0302 clinical medicine, Cancer immunotherapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Neoplasms, medicine, Humans, In patient, 030304 developmental biology, Medicine(all), 0303 health sciences, geography, Summit, geography.geographical_feature_category, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Biochemistry, Genetics and Molecular Biology(all), business.industry, lcsh:R, Cancer, General Medicine, Public relations, medicine.disease, 3. Good health, Clinical trial, Immunotherapy, Neoplasms/therapy, Translational Medical Research, 030220 oncology & carcinogenesis, Immunology, Commentary, Working group, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer. © 2011 Fox et al; licensee BioMed Central Ltd.

Published
2011
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5. HLA-A*0201-restricted CEA-derived peptide CAP1 is not a suitable target for T-cell-based immunotherapy

Author

Aurélie Drouet, Jean Baptiste Latouche, Thierry Frebourg, Emilie Fauquembergue, Jérôme Leprince, Mireille Desille, Florian Cabillic, Véronique Catros, Hubert Vaudry, Olivier Toutirais, Licia Rivoltini, Cécile Thomas de La Pintière, Stéphanie Baert-Desurmont, Richard Sesboüé, David Tougeron, Matthieu Le Gallo, Manuela Iero, Biothérapies Innovantes, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Appareil Digestif Environnement Nutrition (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Microenvironnement et remodelage, Foie, métabolismes et cancer, 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 )-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 )-Biothérapies Innovantes, 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 ), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori-IRCCS Foundation, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Foie, métabolismes et cancer, 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 )-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 )-Biothérapies Innovantes, Université de Rennes - Faculté de Médecine (UR Médecine), Université de Rennes (UR), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Université de Rennes (UR)-Foie, métabolismes et cancer, 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 )-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 ), 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 ), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes]-Université de Rennes - Faculté de Médecine (UR Médecine), and Université de Rennes (UR)-Foie, métabolismes et cancer

Subjects
MESH: Carcinoma, Cancer Research, MESH: 3T3 Cells, medicine.medical_treatment, artificial antigen presenting cells, MESH: HT29 Cells, Lymphocyte Activation, Immunotherapy, Adoptive, Epitope, Mice, 0302 clinical medicine, Carcinoembryonic antigen, Transduction, Genetic, MESH: HLA-A2 Antigen, Immunology and Allergy, Cytotoxic T cell, MESH: Animals, Cloning, Molecular, Antigen Presentation, 0303 health sciences, biology, 3T3 Cells, MESH: Transduction, Genetic, medicine.anatomical_structure, 030220 oncology & carcinogenesis, MESH: Immunotherapy, Adoptive, MESH: Oligopeptides, HT29 Cells, Oligopeptides, MESH: Carcinoembryonic Antigen, T cell, retroviral transduction, Immunology, Antigen presentation, T-cell-based immunotherapy, 03 medical and health sciences, Artificial antigen presenting cells, HLA-A2 Antigen, medicine, Animals, Humans, MESH: Cloning, Molecular, Antigen-presenting cell, MESH: Lymphocyte Activation, MESH: Mice, MESH: HLA-A Antigens, 030304 developmental biology, Pharmacology, MESH: Humans, HLA-A Antigens, carcinoembryonic antigen, cytotoxic T cells, Carcinoma, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Immunotherapy, CAP1 peptide, MESH: Antigen Presentation, biology.protein, MESH: T-Lymphocytes, Cytotoxic, T-Lymphocytes, Cytotoxic
Abstract

International audience; Carcinoembryonic antigen (CEA) is a potential target for antigen-specific immunotherapy, as it is frequently overexpressed in human carcinomas. Moreover, an epitope derived from CEA, designated CAP1 (YLSGANLNL), has been proposed as naturally processed and presented by tumors in the human leukocyte antigen (HLA)-A*0201 context. Our aim was to fully characterize and assess the clinical relevance of the HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) response against CEA. Stable and potent artificial antigen presenting cells (AAPCs) were used to evaluate T-cell response against CEA. These cells efficiently activate CTLs against tumor-derived epitopes after transduction with the antigenic peptides or full-length proteins. We found that AAPCs genetically modified to express CAP1, the agonist peptide CAP1-6D, or the whole CEA protein were not able to activate CAP1-specific CTLs from HLA-A*0201+ healthy donors or patients with colorectal carcinoma, even after multiple stimulations. In addition, we showed that a CAP1-specific T-cell clone, obtained after multiple stimulations of T cells of a HLA-A*0201+ healthy donor in vitro with autologous antigen presenting cells, recognized CEA(-) HLA-A*0201+ tumors transduced with a minigene encoding CAP1 but failed to react against HLA-A*0201+ tumor cells expressing CEA. Finally, AAPCs expressing the whole CEA protein did not induce any specific CTL response against CEA+ HLA-A*0201+ tumor cells highlighting the potential difficulty of mounting an efficacious T-cell response against this autoantigen. Altogether, our data indicate that CAP1 is not efficiently processed and presented by CEA+ tumor cells, and therefore, is not an appropriate target for T-cell-based immunotherapy.

Published
2010
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6. Emerging concepts in biomarker discovery; the US-Japan Workshop on Immunological Molecular Markers in Oncology

Author

A. Karolina Palucka, Anatoli Malyguine, Yutaka Kawakami, Yingdong Zhao, Mai-Britt Zocca, Lisa H. Butterfield, Michele Maio, Hiroya Takeuchi, David F. Stroncek, Damien Chaussabel, John M. Kirkwood, Howard Streicher, Wolf Hervé Fridman, Noriyuki Sato, Oleg Eremin, Lance A. Liotta, Hisashi Wada, Peter P. Lee, Thomas O. Kleen, Hisahiro Matsubara, Tomonori Yaguchi, Mohammed Kashani-Sabet, Emanuel F. Petricoin, Ena Wang, Kohzoh Imai, James W. Jacobson, Paul V Lehmann, Masahisa Jinushi, Antoni Ribas, Marimo Sato, Hiroshi Shiku, Kazunori Kato, Mary L. Disis, Magdalena Thurin, Hideaki Tahara, Julia Wulfkuhle, Yoshihiko Hirohashi, Stefan Ambs, Bernard A. Fox, Xifeng Wu, Shawmarie Mayrand-Chung, Giuseppe Masucci, Minoru Toyota, Hiroyoshi Nishikawa, Yuichiro Doki, Yasunori Akutsu, Akira Kanamoto, Benjamin Zeskind, Samir N. Khleif, Francesco M. Marincola, Michael T. Lotze, Zoltan Pos, Licia Rivoltini, Jon M. Wigginton, Craig L. Slingluff, Kiminori Nakamura, BMC, Ed., Department of Surgery and Bioengineering, The University of Tokyo (UTokyo)-Institute of Medical Science-Advanced Clinical Research Center, Cancer Diagnosis Program, National Institutes of Health (NIH)-National Cancer Institute (NCI), Infectious Disease and Immunogenetics Section (IDIS), National Institutes of Health (NIH)-Department of Transfusion Medicine-Clinical Center and Center for Human Immunology (CHI), Departments of Medicine, Surgery and Immunology, Division of Hematology Oncology-University of Pittsburgh Cancer Institute, Tumor Vaccine Group, University of Washington [Seattle]-Center for Translational Medicine in Women's Health, Department of Molecular Microbiology and Immunology, Oregon Health and Science University [Portland] (OHSU)-Robert W Franz Research Center-Earle A Chiles Research Institute-Providence Portland Medical Center, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Cancer Vaccine Section, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute (NCI), Discovery Medicine-Oncology, Bristol-Myers Squibb Inc., Laboratory of Human Carcinogenesis, National Institutes of Health (NIH)-National Cancer Institute (NCI)-Center of Cancer Research, Department of Frontier Surgery, Chiba University-Graduate School of Medicine, Baylor Institute for Immunology Research (BIIR), Department of Surgery, Osaka University [Osaka]-Graduate School of Medicine, Section of Surgery, Biomedical Research Unit-Nottingham Digestive Disease Centre-University of Nottingham, UK (UON), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), 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)-Centre National de la Recherche Scientifique (CNRS), Sapporo Medical University, Melanoma Clinic, University of California (UC), Department of Molecular Medicine, School of Medicine-Sapporo Medical University, Division of Cellular Signaling, Institute for Advanced Medical Research-Keio University School of Medicine [Tokyo, Japan], Cellular Technology Ltd, Shaker Heights, Department of Molecular Pathology and Microbiology, Center for Applied Proteomics and Molecular Medicine-George Mason University [Fairfax], Illman Cancer Center, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Medical Oncology and Immunotherapy, Istituto Toscano Tumori-Department. of Oncology-Hospital of Siena, Cancer Bioimmunotherapy Unit, Department of Medical Oncology-Centro di Riferimento Oncologico, IRCCS, Laboratory of Cell Mediated Immunity, SAIC-Frederick-Inc. NCI-Frederick, Department of Oncology-Pathology, karolinska institute, The Biomarkers Consortium (BC), Public-Private Partnership Program-Office of the Director-National Institute of Health (NIH), Department of Cancer Vaccine & Department of Immuno-gene Therapy, Mie University, Department of Medicine, Jonsson Comprehensive Cancer Center, Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori-IRCCS Foundation, Department of Pathology, Sapporo Medical University School of Medicine, Sapporo Medical University-Sapporo Medical University, Division of Surgical Oncology-University of Virginia School of Medicine, Cancer Therapy Evaluation Program, National Institutes of Health (NIH)-National Cancer Institute (NCI)-DCTD, Cell Therapy Section (CTS), Department of Transfusion Medicine-Clinical Center-National Institutes of Health, Keio University School of Medicine [Tokyo, Japan], Department of Biochemistry, Department of Epidemiology, The University of Texas Health Science Center at Houston (UTHealth)-The University of Texas M.D. Anderson Cancer Center [Houston], Immuneering Corporation, Biometric Research Branch, DanDritt Biotech A/S, University of California, Keio University School of Medicine [Tokyo, Japan]-Institute for Advanced Medical Research, The University of Tokyo-Institute of Medical Science-Advanced Clinical Research Center, Infectious Disease and Immunogenetics Section ( IDIS ), Oregon Health and Science University-Robert W Franz Research Center-Earle A Chiles Research Institute-Providence Portland Medical Center, Stanford University School of Medicine [Stanford], Stanford University [Stanford], National Cancer Institute (NCI)-, National Institutes of Health (NIH), Baylor Institute for Immunology Research ( BIIR ), Biomedical Research Unit-Nottingham Digestive Disease Centre-University of Nottingham, UK ( UON ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), School of Medicine, Keio University School of Medicine-Institute for Advanced Medical Research, University of Pittsburgh, The Biomarkers Consortium ( BC ), Mie University Graduate School of Medicine, Cell Therapy Section ( CTS ), Keio University School of Medicine, and University of Texas at Houston [Houston] ( UTHealth ) -MD Anderson Cancer Center

Subjects
Oncology, Standardization, medicine.medical_treatment, lcsh:Medicine, MESH : Japan, Disease, 0302 clinical medicine, Cancer immunotherapy, MESH : Tumor Markers, Biological, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Neoplasms, Biomarker discovery, MESH: Japan, Medicine(all), 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Medicine, 3. Good health, MESH: Reproducibility of Results, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH : Biomedical Research, medicine.medical_specialty, MESH : National Cancer Institute (U.S.), MESH : United States, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH : United States Food and Drug Administration, MESH: National Cancer Institute (U.S.), General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Internal medicine, MESH: United States Food and Drug Administration, medicine, MESH: United States, 030304 developmental biology, MESH: Humans, Biochemistry, Genetics and Molecular Biology(all), business.industry, Task force, MESH : Reproducibility of Results, MESH: Biomedical Research, lcsh:R, MESH : Humans, Cancer, Immunotherapy, medicine.disease, MESH : Neoplasms, Clinical trial, MESH: Tumor Markers, Biological, Commentary, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Supported by the Office of International Affairs, National Cancer Institute (NCI), the "US-Japan Workshop on Immunological Biomarkers in Oncology" was held in March 2009. The workshop was related to a task force launched by the International Society for the Biological Therapy of Cancer (iSBTc) and the United States Food and Drug Administration (FDA) to identify strategies for biomarker discovery and validation in the field of biotherapy. The effort will culminate on October 28th 2009 in the "iSBTc-FDA-NCI Workshop on Prognostic and Predictive Immunologic Biomarkers in Cancer", which will be held in Washington DC in association with the Annual Meeting. The purposes of the US-Japan workshop were a) to discuss novel approaches to enhance the discovery of predictive and/or prognostic markers in cancer immunotherapy; b) to define the state of the science in biomarker discovery and validation. The participation of Japanese and US scientists provided the opportunity to identify shared or discordant themes across the distinct immune genetic background and the diverse prevalence of disease between the two Nations. Converging concepts were identified: enhanced knowledge of interferon-related pathways was found to be central to the understanding of immune-mediated tissue-specific destruction (TSD) of which tumor rejection is a representative facet. Although the expression of interferon-stimulated genes (ISGs) likely mediates the inflammatory process leading to tumor rejection, it is insufficient by itself and the associated mechanisms need to be identified. It is likely that adaptive immune responses play a broader role in tumor rejection than those strictly related to their antigen-specificity; likely, their primary role is to trigger an acute and tissue-specific inflammatory response at the tumor site that leads to rejection upon recruitment of additional innate and adaptive immune mechanisms. Other candidate systemic and/or tissue-specific biomarkers were recognized that might be added to the list of known entities applicable in immunotherapy trials. The need for a systematic approach to biomarker discovery that takes advantage of powerful high-throughput technologies was recognized; it was clear from the current state of the science that immunotherapy is still in a discovery phase and only a few of the current biomarkers warrant extensive validation. It was, finally, clear that, while current technologies have almost limitless potential, inadequate study design, limited standardization and cross-validation among laboratories and suboptimal comparability of data remain major road blocks. The institution of an interactive consortium for high throughput molecular monitoring of clinical trials with voluntary participation might provide cost-effective solutions.

Published
2009
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7. Preclinical pharmacology of patient-derived extracellular vesicles for the intraoperative imaging of tumors.

Author

Villa A, Crescenti D, De Mitri Z, Crippa E, Rosa S, Rizzi N, Shojaei-Ghahrizjani F, Rebecchi M, Vincenti S, Selmin F, Brunialti E, Simonotti N, Maspero M, Dei Cas M, Recordati C, Paltrinieri S, Giordano A, Paroni R, Galassi M, Ladisa V, Arienti F, Cilurzo F, Mazzaferro V, and Ciana P

Subjects
Animals, Humans, Mice, Tissue Distribution, Fluorescent Dyes, Female, Extracellular Vesicles, Indocyanine Green administration & dosage, Indocyanine Green pharmacokinetics, Neoplasms diagnostic imaging, Neoplasms surgery, Neoplasms therapy
Abstract

Extracellular vesicles (EVs) derived from the plasma of oncological patients exhibit significant tumor-targeting properties, unlike those from healthy individuals. We have previously shown the feasibility of formulating the near-infrared (NIR) fluorescent dye indocyanine green (ICG) with patient-derived extracellular vesicles (PDEVs) for selective delivery to neoplastic tissue. This staining protocol holds promise for clinical application in intraoperative tumor margin imaging, enabling precise neoplastic tissue resection. To this end, we propose the ONCOGREEN protocol, involving PDEV isolation, ICG loading, and reinfusion into the same patients. Methods : By in vivo studies on mice, we outlined key pharmacological parameters of PDEVs-ICG for intraoperative tumor imaging, PDEV biodistribution kinetics, and potential treatment-related toxicological effects. Additionally, we established a plasmapheresis-based protocol for isolating autologous PDEVs, ensuring the necessary large-scale dosage for human treatment. A potential lyophilization-based preservation method was also explored to facilitate the storage and transport of PDEVs. Results : The study identified the effective dose of PDEVs-ICG necessary for clear intraoperative tumor margin imaging. The biodistribution kinetics of PDEVs showed favorable targeting to neoplastic tissues, without off-target distribution. Toxicological assessments revealed no significant adverse effects associated with the treatment. The plasmapheresis-based isolation protocol successfully yielded a sufficient quantity of autologous PDEVs, and the lyophilization preservation method maintained the functional integrity of PDEVs for subsequent clinical application. Conclusions : Our research lays the groundwork for the direct clinical application of autologous PDEVs, initially focusing on intraoperative imaging. Utilizing autologous PDEVs has the potential to accelerate the integration of EVs as a targeted delivery tool for anti-neoplastic agents to cancerous tissue. This approach promises to enhance the precision of neoplastic tissue resection and improve overall surgical outcomes for oncological patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Published
2024
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8. Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications.

Author

Martin-Serrano MA, Kepecs B, Torres-Martin M, Bramel ER, Haber PK, Merritt E, Rialdi A, Param NJ, Maeda M, Lindblad KE, Carter JK, Barcena-Varela M, Mazzaferro V, Schwartz M, Affo S, Schwabe RF, Villanueva A, Guccione E, Friedman SL, Lujambio A, Tocheva A, Llovet JM, Thung SN, Tsankov AM, and Sia D

Subjects
Humans, Animals, Mice, Disease Models, Animal, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Bile Ducts, Intrahepatic metabolism, Bile Ducts, Intrahepatic pathology, Tumor Microenvironment, Bile Duct Neoplasms pathology, Cholangiocarcinoma pathology
Abstract

Objective: The diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed. We aimed to generate a novel molecular iCCA classifier that incorporates elements of the stroma, tumour and immune microenvironment ('STIM' classification)., Design: We applied virtual deconvolution to transcriptomic data from ~900 iCCAs, enabling us to devise a novel classification by selecting for the most relevant TME components. Murine models were generated through hydrodynamic tail vein injection and compared with the human disease., Results: iCCA is composed of five robust STIM classes encompassing both inflamed (35%) and non-inflamed profiles (65%). The inflamed classes, named immune classical (~10%) and inflammatory stroma (~25%), differ in oncogenic pathways and extent of desmoplasia, with the inflammatory stroma showing T cell exhaustion, abundant stroma and KRAS mutations (p<0.001). Analysis of cell-cell interactions highlights cancer-associated fibroblast subtypes as potential mediators of immune evasion. Among the non-inflamed classes, the desert-like class (~20%) harbours the lowest immune infiltration with abundant regulatory T cells (p<0.001), whereas the hepatic stem-like class (~35%) is enriched in 'M2-like' macrophages, mutations in IDH1/2 and BAP1, and FGFR2 fusions. The remaining class ( tumour classical : ~10%) is defined by cell cycle pathways and poor prognosis. Comparative analysis unveils high similarity between a KRAS/p19 murine model and the inflammatory stroma class (p=0.02). The KRAS-SOS inhibitor, BI3406, sensitises a KRAS -mutant iCCA murine model to anti-PD1 therapy., Conclusions: We describe a comprehensive TME-based stratification of iCCA. Cross-species analysis establishes murine models that align closely to human iCCA for the preclinical testing of combination strategies., Competing Interests: Competing interests: JML is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Eli Lilly, Bayer HealthCare Pharmaceuticals, Bristol-Myers Squibb, Eisai Inc, Celsion Corporation, Exelixis, Merck, Ipsen, Genentech, Roche, Glycotest, Nucleix, Sirtex, Mina Alpha Ltd and AstraZeneca. AV has received consulting fees from Genentech, Guidepoint, Fujifilm, Boehringer Ingelheim, FirstWord, and MHLife Sciences; advisory board fees from Exact Sciences, Nucleix, Gilead and NGM Pharmaceuticals; and research support from Eisai., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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9. Increased Sensitivity of Computed Tomography Scan for Neoplastic Tissues Using the Extracellular Vesicle Formulation of the Contrast Agent Iohexol.

Author

Vincenti S, Villa A, Crescenti D, Crippa E, Brunialti E, Shojaei-Ghahrizjani F, Rizzi N, Rebecchi M, Dei Cas M, Del Sole A, Paroni R, Mazzaferro V, and Ciana P

Abstract

Computed tomography (CT) is a diagnostic medical imaging modality commonly used to detect disease and injury. Contrast agents containing iodine, such as iohexol, are frequently used in CT examinations to more clearly differentiate anatomic structures and to detect and characterize abnormalities, including tumors. However, these contrast agents do not have a specific tropism for cancer cells, so the ability to detect tumors is severely limited by the degree of vascularization of the tumor itself. Identifying delivery systems allowing enrichment of contrast agents at the tumor site would increase the sensitivity of detection of tumors and metastases, potentially in organs that are normally inaccessible to contrast agents, such as the CNS. Recent work from our laboratory has identified cancer patient-derived extracellular vesicles (PDEVs) as effective delivery vehicles for targeting diagnostic drugs to patients' tumors. Based on this premise, we explored the possibility of introducing iohexol into PDEVs for targeted delivery to neoplastic tissue. Here, we provide preclinical proof-of-principle for the tumor-targeting ability of iohexol-loaded PDEVs, which resulted in an impressive accumulation of the contrast agent selectively into the neoplastic tissue, significantly improving the ability of the contrast agent to delineate tumor boundaries.

Published
2022
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10. The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.

Author

Karlsen TH, Sheron N, Zelber-Sagi S, Carrieri P, Dusheiko G, Bugianesi E, Pryke R, Hutchinson SJ, Sangro B, Martin NK, Cecchini M, Dirac MA, Belloni A, Serra-Burriel M, Ponsioen CY, Sheena B, Lerouge A, Devaux M, Scott N, Hellard M, Verkade HJ, Sturm E, Marchesini G, Yki-Järvinen H, Byrne CD, Targher G, Tur-Sinai A, Barrett D, Ninburg M, Reic T, Taylor A, Rhodes T, Treloar C, Petersen C, Schramm C, Flisiak R, Simonova MY, Pares A, Johnson P, Cucchetti A, Graupera I, Lionis C, Pose E, Fabrellas N, Ma AT, Mendive JM, Mazzaferro V, Rutter H, Cortez-Pinto H, Kelly D, Burton R, Lazarus JV, Ginès P, Buti M, Newsome PN, Burra P, and Manns MP

Subjects
Europe epidemiology, Health Policy, Humans, Liver Diseases economics, Liver Diseases mortality, Liver Diseases epidemiology, Liver Diseases prevention & control, Mortality, Premature
Abstract

Competing Interests: Declarations of interests IG received support from Fundacion de Investigacion sanitaria and was cofunded by Instituto Carlos III for the present manuscript; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences, Intercept, and AbbVie; and support for attending meetings or travel from Intercept and Gilead Sciences. EB received grants or contracts from Gilead Sciences; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences and Novo Nordisk; and participated on Data Safety Monitoring Boards or advisory boards for Bristol Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Intercept, Inventiva, and Novo Nordisk. MC received grants or contracts and support for attending meetings or travel from the OECD programme of work for public health. RF received grants or contracts from Gilead Sciences, AbbVie, Roche, and Merck Sharp & Dohme; consulting fees from Gilead Sciences, AbbVie, Janssen, and Pfizer; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences, AbbVie, Merck Sharp & Dohme, and AdamedPG; and support for attending meetings or travel from Gilead Sciences, AbbVie, and Merck Sharp & Dohme. JVL received grants or contracts from AbbVie, Gilead Sciences, Merck Sharp & Dohme; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Gilead Sciences, Intercept, Janssen, and Merck Sharp & Dohme. AL received grants or contracts from the OECD programme of work for public health, which is supported by Ministries of Health, National Governmental Institutions, and intergovernmental organisations, as well as support to present results from OECD analyses to meetings, seminars, and workshops. CL received grants or contracts from the University of Oxford, UK National Centre for Smoking Cessation and Training, and Horizon 2020 of the European Commission; received royalties or licenses from and has patents planned, issued, or pending with Olvos Science (Cretan Iama); received payment for expert testimony from WHO and the European Commission; and participated on Data Safety Monitoring Boards or advisory boards for Merck Sharp & Dohme, Pfizer Hellas, Vianex. MPM received grants or contracts from AbbVie, Eiger BioPharmaceuticals, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Intercept, Merck Sharp & Dohme, and Roche; received consulting fees from AbbVie, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Intercept, Merck Sharp & Dohme, Novartis, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Merck Sharp & Dohme, and Roche; received support for attending meetings or travel from AbbVie, Bristol Myers Squibb, Dr Falk Pharma, Gilead Sciences, Merck Sharp & Dohme, and Roche; participated on Data Safety Monitoring Boards or advisory boards for Eiger, Dr Falk Pharma, Gilead Sciences, and Roche; and is Associate Editor for Clinical Gastroenterology and Hepatology. NKM received grants or contracts from Merck Sharp & Dohme and Gilead Sciences. MN received grants or contracts from Gilead Sciences, Merck Sharp & Dohme, AbbVie, and Janssen; and was President of the World Hepatitis Alliance (2018–20). CYP received grants or contracts from Takeda, Pliant, and Gilead Sciences; consulting fees from Pliant and Shire (Takeda); and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Tillotts Pharma, and Pfizer. BSa received grants or contracts from Bristol Myers Squibb and Sirtex Medical; received consulting fees from Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Sirtex Medical, TERUMO, H3 Biomedicine, Incyte, Ipsen, Lilly, and Roche; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Bristol Myers Squibb, Sirtex Medical, TERUMO, Incyte, and Ipsen; and participated on Data Safety Monitoring Boards or advisory boards for Adaptimmune, AstraZeneca, Bayer, Bristol Myers Squibb, BTG, Sirtex Medical, TERUMO, H3 Biomedicine, Incyte, Ipsen, Lilly, and Roche. CS received grants or contracts from BiomX and Galapagos; consulting fees from BiomX; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Falk Foundation. NSc received grants or contracts from Gilead Sciences. MS-B received grants or contracts from the European Commission. CT received grants or contracts from Merck Sharp & Dohme; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences and AbbVie. RB received consulting fees from WHO. HC-P received consulting fees from Orphalan; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Orphalan, Novo Nordisk, GENFIT, Promethera Biosciences, and Intercept. GD received consulting fees from Aligos Therapeutics, Roche, Arbutus Biopharma, Gilead Sciences, Shionogi, Antios Therapeutics; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences; and participated on Data Safety Monitoring Boards or advisory boards for Janssen, Pharmaceuticals, GlaxoSmithKline, and Aligos Therapeutics. THK received consulting fees from Engitix and Intercept; has stock or stock options in Ultimovacs; received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences, Novartis, and AlfaSigma; and is on the board of the Biomedical Alliance in Europe. ES received consulting fees from Albireo, Mirum, and Alexion; received support for attending meetings or travel from Astellas; participated on Data Safety Monitoring Boards or advisory boards for Albireo, Alexion, and Mirum; and received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Albireo. PB received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Kedrion Biopharma, Biotest, and Chiesi Farmaceutici. MB received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences and AbbVie. SJH received payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead Sciences. NF participated on Data Safety Monitoring Boards or advisory boards for Intercept in relation to NAFLD. GM participated on Data Safety Monitoring Boards or advisory boards for Gilead Sciences, Novartis, Pfizer, and AstraZeneca. All other authors declare no competing interests.

Published
2022
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11. Transplantation of autologous extracellular vesicles for cancer-specific targeting.

Author

Villa A, Garofalo M, Crescenti D, Rizzi N, Brunialti E, Vingiani A, Belotti P, Sposito C, Franzè S, Cilurzo F, Pruneri G, Recordati C, Giudice C, Giordano A, Tortoreto M, Beretta G, Stefanello D, Manenti G, Zaffaroni N, Mazzaferro V, and Ciana P

Subjects
Animals, Apoptosis, Breast Neoplasms pathology, Case-Control Studies, Cell Proliferation, Colorectal Neoplasms pathology, Dogs, Female, Humans, Liver Neoplasms secondary, Male, Mice, Mice, Inbred C57BL, Mice, SCID, Tissue Distribution, Transplantation, Autologous, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Breast Neoplasms therapy, Colorectal Neoplasms therapy, Extracellular Vesicles transplantation, Liver Neoplasms therapy
Abstract

Nano- and microsized extracellular vesicles (EVs) are naturally occurring cargo-bearing packages of regulatory macromolecules, and recent studies are increasingly showing that EVs are responsible for physiological intercellular communication. Nanoparticles encapsulating anti-tumor theranostics represent an attractive "exosome-interfering" strategy for cancer therapy. Methods : Herein, by labeling plasma-derived EVs with indocyanine green (ICG) and following their biodistribution by in vivo and ex vivo imaging, we demonstrate the existence of nanoparticles with a highly selective cancer tropism in the blood of colorectal cancer (CRC) patients but not in that of healthy volunteers. Results : In CRC patient-derived xenograft (PDX) mouse models, we show that transplanted EVs recognize tumors from the cognate nanoparticle-generating individual, suggesting the theranostic potential of autologous EVs encapsulating tumor-interfering molecules. In large canine breeds bearing spontaneous malignant skin and breast tumors, the same autologous EV transplantation protocol shows comparable safety and efficacy profiles. Conclusions : Our data show the existence of an untapped resource of intercellular communication present in the blood of cancer patients, which represents an efficient and highly biocompatible way to deliver molecules directly to the tumor with great precision. The novel EV-interfering approach proposed by our study may become a new research direction in the complex interplay of modern personalized cancer therapy., Competing Interests: Competing Interests: Al.V., M.G., V.M. and P.C. are coinventors of the patent n. IT 102019000007785 filed on May 5th 2019, at the Italian patent office: UIBM., (© The author(s).)

Published
2021
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13. The Italian multicentre dosimetric study for lesion dosimetry in 223 Ra therapy of bone metastases: Calibration protocol of gamma cameras and patient eligibility criteria.

Author

Pacilio M, Cassano B, Chiesa C, Giancola S, Ferrari M, Pettinato C, Amato E, Fioroni F, Lorenzon L, Pellegrini R, Di Castro E, Pani R, and Cremonesi M

Subjects
Calibration, Humans, Italy, Patient Selection, ROC Curve, Bone Neoplasms radiotherapy, Bone Neoplasms secondary, Gamma Cameras, Radiometry instrumentation, Radium therapeutic use
Abstract

Purpose: The aims of this work were to explore patient eligibility criteria for dosimetric studies in 223 Ra therapy and evaluate the effects of differences in gamma camera calibration procedures into activity quantification., Methods: Calibrations with 223 Ra were performed with four gamma cameras (3/8-inch crystal) acquiring planar static images with double-peak (82 and 154keV, 20% wide) and MEGP collimator. The sensitivity was measured in air by varying activity, source-detector distance, and source diameter. Transmission curves were measured for attenuation/scatter correction with the pseudo-extrapolation number method, varying the experimental setup. 223 Ra images of twenty-five patients (69 lesions) were acquired to study the lesions visibility. Univariate ROC analysis was performed considering visible/non visible lesions on 223 Ra images as true positive/true negative group, and using as score value the lesion/soft tissue contrast ratio (CR) derived from 99m Tc-MDP WB scan., Results: Sensitivity was nearly constant varying activity and distance (maximum s.d.=2%). Partial volume effects were negligible for object area ⩾960mm 2 . Transmission curve measurements are affected by experimental setup and source size, leading to activity quantification errors up to 20%. The ROC analysis yielded an AUC of 0.972 and an optimal threshold of CR of 10, corresponding to an accuracy of 92%., Conclusion: The minimum calibration protocol requires sensitivity and transmission curve measurements varying the object size, performing a careful procedure standardisation. Lesions with 99m Tc-MDP CR higher than 10, not overlapping the GI tract, are generally visible on 223 Ra images acquired at 24h after the administration, and possibly eligible for dosimetric studies., (Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Published
2016
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14. Serum soluble urokinase-type plasminogen activator receptor as a serum marker of inflammatory response that leads to tissue damage and surgical complication.

Author

Tognoli E, Luigi Giuseppe Leoni M, Morelli D, Sottotetti E, Martinetti A, Signoroni S, Galeone C, and Gallino G

Subjects
Biomarkers blood, Female, Humans, Male, Predictive Value of Tests, ROC Curve, Retrospective Studies, Up-Regulation, Anastomotic Leak blood, Inflammation blood, Inflammation pathology, Inflammation Mediators blood, Postoperative Complications blood, Receptors, Urokinase Plasminogen Activator blood
Abstract

Unrestrained activation of the proteolytic systems in anastomotic tissue during repair has been implicated in the pathogenesis of anastomotic leakage. We hypothesized that this mechanism may promote an up-regulation of the urokinase-type plasminogen activator system and a spillover of soluble urokinase-type plasminogen activator receptor (suPAR) into blood. In this retrospective analysis patients with anastomotic leakage were compared with a group of matched uncomplicated patients. Anastomotic leakage complicated patients had significantly higher suPAR (p = 0.04) levels until day 3 after surgery. The area under the receiver-operating characteristic (ROC) for suPAR was higher than that CRP (0.874 vs. 0.836). Their analysis suggests the possible use of suPAR as serum marker to characterize the persistent inflammatory response that lead to tissue damage and surgical complication., (© 2016 by the Wound Healing Society.)

Published
2016
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15. Impact of SPECT corrections on 3D-dosimetry for liver transarterial radioembolization using the patient relative calibration methodology.

Author

Pacilio M, Ferrari M, Chiesa C, Lorenzon L, Mira M, Botta F, Becci D, Torres LA, Coca Perez M, Vergara Gil A, Basile C, Ljungberg M, Pani R, and Cremonesi M

Subjects
Calibration, Computer Simulation, Dose-Response Relationship, Radiation, Embolization, Therapeutic instrumentation, Female, Humans, Imaging, Three-Dimensional instrumentation, Liver diagnostic imaging, Liver radiation effects, Male, Models, Anatomic, Monte Carlo Method, Organotechnetium Compounds, Phantoms, Imaging, Radiometry instrumentation, Radiopharmaceuticals, Radiotherapy instrumentation, Software, Tomography, Emission-Computed, Single-Photon instrumentation, Embolization, Therapeutic methods, Imaging, Three-Dimensional methods, Radiometry methods, Radiotherapy methods, Tomography, Emission-Computed, Single-Photon methods
Abstract

Purpose: Many centers aim to plan liver transarterial radioembolization (TARE) with dosimetry, even without CT-based attenuation correction (AC), or with unoptimized scatter correction (SC) methods. This work investigates the impact of presence vs absence of such corrections, and limited spatial resolution, on 3D dosimetry for TARE., Methods: Three voxelized phantoms were derived from CT images of real patients with different body sizes. Simulations of (99m)Tc-SPECT projections were performed with the SIMIND code, assuming three activity distributions in the liver: uniform, inside a "liver's segment," or distributing multiple uptaking nodules ("nonuniform liver"), with a tumoral liver/healthy parenchyma ratio of 5:1. Projection data were reconstructed by a commercial workstation, with OSEM protocol not specifically optimized for dosimetry (spatial resolution of 12.6 mm), with/without SC (optimized, or with parameters predefined by the manufacturer; dual energy window), and with/without AC. Activity in voxels was calculated by a relative calibration, assuming identical microspheres and (99m)Tc-SPECT counts spatial distribution. 3D dose distributions were calculated by convolution with (90)Y voxel S-values, assuming permanent trapping of microspheres. Cumulative dose-volume histograms in lesions and healthy parenchyma from different reconstructions were compared with those obtained from the reference biodistribution (the "gold standard," GS), assessing differences for D95%, D70%, and D50% (i.e., minimum value of the absorbed dose to a percentage of the irradiated volume). γ tool analysis with tolerance of 3%/13 mm was used to evaluate the agreement between GS and simulated cases. The influence of deep-breathing was studied, blurring the reference biodistributions with a 3D anisotropic gaussian kernel, and performing the simulations once again., Results: Differences of the dosimetric indicators were noticeable in some cases, always negative for lesions and distributed around zero for parenchyma. Application of AC and SC reduced systematically the differences for lesions by 5%-14% for a liver segment, and by 7%-12% for a nonuniform liver. For parenchyma, the data trend was less clear, but the overall range of variability passed from -10%/40% for a liver segment, and -10%/20% for a nonuniform liver, to -13%/6% in both cases. Applying AC, SC with preset parameters gave similar results to optimized SC, as confirmed by γ tool analysis. Moreover, γ analysis confirmed that solely AC and SC are not sufficient to obtain accurate 3D dose distribution. With breathing, the accuracy worsened severely for all dosimetric indicators, above all for lesions: with AC and optimized SC, -38%/-13% in liver's segment, -61%/-40% in the nonuniform liver. For parenchyma, D50% resulted always less sensitive to breathing and sub-optimal correction methods (difference overall range: -7%/13%)., Conclusions: Reconstruction protocol optimization, AC, SC, PVE and respiratory motion corrections should be implemented to obtain the best possible dosimetric accuracy. On the other side, thanks to the relative calibration, D50% inaccuracy for the healthy parenchyma from absence of AC was less than expected, while the optimization of SC was scarcely influent. The relative calibration therefore allows to perform TARE planning, basing on D50% for the healthy parenchyma, even without AC or with suboptimal corrections, rather than rely on nondosimetric methods.

Published
2016
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16. Liver transplantation for adenomatosis: European experience.

Author

Chiche L, David A, Adam R, Oliverius MM, Klempnauer J, Vibert E, Colledan M, Lerut J, Mazzafero VV, Di-Sandro S, Laurent C, Scuderi V, Suc B, Troisi R, Bachelier P, Dumortier J, Gugenheim J, Mabrut JY, Gonzalez-Pinto I, Pruvot FR, Le-Treut YP, Navarro F, Ortiz-de-Urbina J, Salamé E, Spada M, and Bioulac-Sage P

Subjects
Adenoma, Liver Cell pathology, Adult, Carcinoma, Hepatocellular pathology, Clinical Decision-Making methods, Cohort Studies, Europe epidemiology, Female, Glycogen Storage Disease Type I surgery, Humans, Liver Neoplasms pathology, Male, Registries statistics & numerical data, Retrospective Studies, Treatment Outcome, Adenoma, Liver Cell surgery, Carcinoma, Hepatocellular surgery, Liver Neoplasms surgery, Liver Transplantation statistics & numerical data, Rare Diseases surgery
Abstract

The aim of this study was to collect data from patients who underwent liver transplantation (LT) for adenomatosis; to analyze the symptoms, the characteristics of the disease, and the recipient outcomes; and to better define the role of LT in this rare indication. This retrospective multicenter study, based on data from the European Liver Transplant Registry, encompassed patients who underwent LT for adenomatosis between January 1, 1986, and July 15, 2013, in Europe. Patients with glycogen storage disease (GSD) type IA were not excluded. This study included 49 patients. Sixteen patients had GSD, and 7 had liver vascular abnormalities. The main indications for transplantation were either a suspicion of hepatocellular carcinoma (HCC; 15 patients) or a histologically proven HCC (16 patients), but only 17 had actual malignant transformation (MT) of adenomas. GSD status was similar for the 2 groups, except for age and the presence of HCC on explants (P = 0.030). Three patients with HCC on explant developed recurrence after transplantation. We obtained and studied the pathomolecular characteristics for 23 patients. In conclusion, LT should remain an extremely rare treatment for adenomatosis. Indications for transplantation primarily concern the MT of adenomas. The decision should rely on morphological data and histological evidence of MT. Additional indications should be discussed on a case-by-case basis. In this report, we propose a simplified approach to this decision-making process., (© 2016 American Association for the Study of Liver Diseases.)

Published
2016
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17. Iodine-131 metaiodobenzylguanidine (I-131 MIBG) diagnosis and therapy of pheochromocytoma and paraganglioma: current problems, critical issues and presentation of a sample case.

Author

Castellani MR, Aktolun C, Buzzoni R, Seregni E, Chiesa C, Maccauro M, Aliberti GL, Vellani C, Lorenzoni A, and Bombardieri E

Subjects
Humans, Male, Middle Aged, Radionuclide Imaging, Radiopharmaceuticals therapeutic use, Treatment Outcome, 3-Iodobenzylguanidine therapeutic use, Adrenal Gland Neoplasms diagnostic imaging, Adrenal Gland Neoplasms radiotherapy, Image Enhancement methods, Paraganglioma diagnostic imaging, Paraganglioma radiotherapy
Abstract

Iodine-131 metaiodobenzylguanidine (I-131 MIBG) has been used for the diagnosis and treatment of malignant pheochromocytomas (PHEO) and paragangliomas (PGL) since 1980's. Despite increasing amount of experience with iodine-131 (I-131) MIBG therapy, many important questions still exist. In this article, we will discuss the current problems learned from clinical experience in diagnosis and therapy of PHEO/PGL with I-131 MIBG, and present a sample case to emphasize the critical aspects for an optimal treatment strategy.

Published
2013

18. A dosimetric treatment planning strategy in radioembolization of hepatocarcinoma with 90Y glass microspheres.

Author

Chiesa C, Mira M, Maccauro M, Romito R, Spreafico C, Sposito C, Bhoori S, Morosi C, Pellizzari S, Negri A, Civelli E, Lanocita R, Camerini T, Bampo C, Carrara M, Seregni E, Marchianò A, Mazzaferro V, and Bombardieri E

Subjects
Aged, Carcinoma, Hepatocellular diagnosis, Female, Humans, Liver Neoplasms diagnosis, Male, Microspheres, Middle Aged, Radiopharmaceuticals therapeutic use, Radiotherapy Dosage, Retrospective Studies, Treatment Outcome, Brachytherapy methods, Carcinoma, Hepatocellular radiotherapy, Liver Neoplasms radiotherapy, Radiometry methods, Radiotherapy Planning, Computer-Assisted methods, Yttrium Radioisotopes therapeutic use
Abstract

Aim: Our goal was to limit liver toxicity and to obtain good efficacy by developing a dosimetric treatment planning strategy. While several dosimetric evaluations are reported in literature, the main problem of the safety of the treatment is rarely addressed. Our work is the first proposal of a treatment planning method for glass spheres, including both liver toxicity and efficacy issues., Methods: Fifty-two patients (series 1) had been treated for intermediated/advanced hepatocellular carcinoma (HCC) with glass spheres, according to the Therasphere® prescription of 120 Gy averaged on the injected lobe. They were retrospectively evaluated with voxel dosimetry, adopting the local deposition hypothesis. Regions of interest on tumor and non tumor parenchyma were drawn to determine the parenchyma absorbed dose, averaged also on non irradiated voxels, excluding tumor voxels. The relationship between the mean non tumoral parenchyma absorbed dose D and observed liver decompensation was analyzed., Results: Basal Child-Pugh strongly affected the toxicity incidence, which was 22% for A5, 57% for A6, 89% for B7 patients. Restricting the analysis to our numerically richest class (basal Child-Pugh A5 patients), D median values were significantly different between toxic (median 90 Gy) and non toxic treatments (median 58 Gy) at a Mann-Withney test, (P=0.033). Using D as a marker for toxicity, the separation of the two populations in terms of area under ROC curve was 0.75, with 95% C.I. of [0.55-0.95]. The experimental Normal Tissue Complication Probability (NTCP) curve as a function of D resulted in the following values: 0%, 14%, 40%, 67% for D interval of [0-35] Gy, [35-70] Gy, [70-105] Gy, [105-140] Gy., Discussion: A limit of about 70 Gy for the mean absorbed dose to parenchyma was assumed for A5 patients, corresponding to a 14% risk of liver decompensation. This result is applicable only to our administration conditions: glass spheres after a decay interval of 3.75 days. Different safety limit (40 Gy) are published for resin spheres, characterized by higher number of particle per GBq (more uniform irradiation, bigger biological effect for the same absorbed dose)., Conclusion: As result of this study we suggest a constraint of about 70 Gy mean absorbed dose to liver non tumoral parenchyma, corresponding to about 15% probability of radioinduced liver decompensation while still aiming at achieving an absorbed of several hundreds of Gy to lesions.

Published
2012

19. MIBG for diagnosis and therapy of medullary thyroid carcinoma: is there still a role?

Author

Castellani MR, Seregni E, Maccauro M, Chiesa C, Aliberti G, Orunesu E, and Bombardieri E

Subjects
Carcinoma, Medullary pathology, Humans, Neoplasm Metastasis therapy, Neoplasm, Residual diagnosis, Proto-Oncogene Mas, Recurrence, Thyroid Neoplasms pathology, 3-Iodobenzylguanidine therapeutic use, Carcinoma, Medullary diagnosis, Carcinoma, Medullary radiotherapy, Thyroid Neoplasms diagnosis, Thyroid Neoplasms radiotherapy
Abstract

Medullary thyroid carcinoma (MTC) is a relatively rare neuroendocrine tumour originating from the parafollicular C cells and releases calcitonin (hCt), carcinoembryonic antigen (CEA) and occasionally other substances. In 20-30% of cases MTC presents a germline mutation of the RET proto-oncogene and occurs in 3 different hereditary forms: familial MTC, multiple endocrine neoplasia (MEN) 2A and MEN 2B syndrome. Prognosis of MTC is largely related to tumour extension at disease onset. Surgery remains the most effective therapy for potential cure. Overall survival is strictly linked to the occurrence of relapse. After surgery, serum hCt remains the most sensitive test for occult disease. Diagnostic imaging work-up includes ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, as the more frequent sites of recurrence or metastases are cervical and mediastinal lymph nodes, lungs, liver and bone. Nuclear medicine procedures include (111)In-labelled somatostatin analogs, radioiodinated metaiodobenzylguanidine (MIBG), and several PET radiopharmaceuticals. Experience with radionuclide therapy in MTC is restricted to few patients treated with (131)I-MIBG or (90)Y-DOTATOC. Since 1987, 1 027 diagnostic MIBG scans were performed in the Department Department of Diagnostic Imaging and Therapy of the Istituto Nazionale Tumori IRCCS Foundation (Milan, Italy), 85 of which for MTC, with a sensitivity of 38.7% in patients with evidence of disease and 30.7 % if all patients were considered. Since 1994, 13 MTC patients were treated with MIBG with 4 partial responses and 4 stable diseases. Patients with liver or bone involvement responded to therapy and showed long-term partial remission of disease, others showed stability of disease, which was apparently unrelated to therapy. Improvement of efficacy can be achieved through dosimetric calculation of administered activity.

Published
2008

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