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1. Evidence for Highly Variable, Region-Specific Patterns of T-Cell Epitope Mutations Accumulating in Mycobacterium tuberculosis Strains

Author

Arunachalam Ramaiah, Soumya Nayak, Srabanti Rakshit, Abigail L. Manson, Thomas Abeel, Sivakumar Shanmugam, Pravat Nalini Sahoo, Anto Jesuraj Uday Kumar John, Jagadish Chandrabose Sundaramurthi, Sujatha Narayanan, George D'Souza, Paul von Hoegen, Tom H. M. Ottenhoff, Soumya Swaminathan, Ashlee M. Earl, and Annapurna Vyakarnam

Subjects
Mycobacterium tuberculosis, genome sequence, T-cell epitopes, evolution, immune response, TB vaccine, Immunologic diseases. Allergy, RC581-607
Abstract

Vaccines that confer protection through induction of adaptive T-cell immunity rely on understanding T-cell epitope (TCE) evolution induced by immune escape. This is poorly understood in tuberculosis (TB), an ancient, chronic disease, where CD4 T-cell immunity is of recognized importance. We probed 905 functionally validated, curated human CD4 T cell epitopes in 79 Mycobacterium tuberculosis (Mtb) whole genomes from India. This screen resulted in identifying 64 mutated epitopes in these strains initially using a computational pipeline and subsequently verified by single nucleotide polymorphism (SNP) analysis. SNP based phylogeny revealed the 79 Mtb strains to cluster to East African Indian (EAI), Central Asian Strain (CAS), and Beijing (BEI) lineages. Eighty-nine percent of the mutated T-cell epitopes (mTCEs) identified in the 79 Mtb strains from India has not previously been reported. These mTCEs were encoded by genes with high nucleotide diversity scores including seven mTCEs encoded by six antigens in the top 10% of rapidly divergent Mtb genes encoded by these strains. Using a T cell functional assay readout, we demonstrate 62% of mTCEs tested to significantly alter CD4 T-cell IFNγ and/or IL2 secretion with associated changes in predicted HLA-DR binding affinity: the gain of function mutations displayed higher predicted HLA-DR binding affinity and conversely mutations resulting in loss of function displayed lower predicted HLA-DR binding affinity. Most mutated antigens belonged to the cell wall/cell processes, and, intermediary metabolism and respiration families though all known Mtb proteins encoded mutations. Analysis of the mTCEs in an SNP database of 5,310 global Mtb strains identified 82% mTCEs to be significantly more prevalent in Mtb strains isolated from India, including 36 mTCEs identified exclusively in strains from India. These epitopes had a significantly higher predicted binding affinity to HLA-DR alleles that were highly prevalent in India compared to HLA-DR alleles rare in India, highlighting HLA-DR maybe an important driver of these mutations. This first evidence of region-specific TCE mutations potentially employed by Mtb to escape host immunity has important implications for TB vaccine design.

Published
2019
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2. 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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3. Universal mapping of humoral immune response using a versatile high-content and high-density peptide microarray

Author

Paul von Hoegen, Holger Wenschuh, Ulf Reimer, Dan H. Barouch, Tobias Knaute, Janina Seznec, and Nikolaus Pawlowski

Subjects
biology, business.industry, Vaccine trial, Computational biology, Bioinformatics, Virus, Vaccination, Infectious Diseases, Immune system, Antigen, Virology, Poster Presentation, biology.protein, Medicine, Peptide microarray, Antibody, DNA microarray, business
Abstract

Background Humoral immune responses are often the hallmark of efficient vaccines. The recent RV144 vaccine trial has turned attention to the stimulation of humoral immune response as a potential mode of action for HIV vaccines. Therefore, detailed monitoring of antibody reactivities in patient specimens before and after vaccination is crucial. The determination of these reactivities on a sub-protein level provides information on the site of antigen/antibody interaction. In contrast to assays relying on whole antigens such as ELISA, peptide microarrays are efficient tools to deliver such information. Besides, complex peptide libraries can cover HIV sequence diversity, a special challenge provided by this virus.

Published
2012

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