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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
0301 basic medicine, genome sequence, Epitopes, T-Lymphocyte, Epitope, immune response, Epitopes, 0302 clinical medicine, Immunology and Allergy, 2.1 Biological and endogenous factors, Public Health Surveillance, Phylogeny, Original Research, Genetics, Immunity, Cellular, Genome, Bacterial, Genomics, Single Nucleotide, Antigenic Variation, Biological Evolution, 3. Good health, medicine.anatomical_structure, Infectious Diseases, Medical Microbiology, Host-Pathogen Interactions, HIV/AIDS, Infection, Biotechnology, lcsh:Immunologic diseases. Allergy, dbSNP, T cell, Immunology, T-cell epitopes, India, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Mycobacterium tuberculosis, Vaccine Related, 03 medical and health sciences, Interferon-gamma, Immune system, Rare Diseases, Antigen, evolution, medicine, Humans, Tuberculosis, Antigens, Polymorphism, Gene, Centre for Infectious Disease Research, Alleles, Antigens, Bacterial, Prevention, Histocompatibility Antigens Class II, Immunity, TB vaccine, biology.organism_classification, 030104 developmental biology, T-Lymphocyte, Mutation, Immunization, Cellular, lcsh:RC581-607, Genome, Bacterial, 030215 immunology
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 IFN gamma 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. Synergistic role of type I interferons in the induction of protective cytotoxic T lymphocytes

Author

Paul von Hoegen

Subjects
Antigens, Differentiation, T-Lymphocyte, Cytotoxicity, Immunologic, Immunology, Interferon-beta, Biology, Recombinant Proteins, In vitro, Mice, Cytolysis, CTL, Immune system, Lytic cycle, Mice, Inbred DBA, In vivo, Interferon, Interferon Type I, Tumor Cells, Cultured, medicine, Cancer research, Animals, Immunology and Allergy, Cytotoxic T cell, T-Lymphocytes, Cytotoxic, medicine.drug
Abstract

Differentiation of cytolytic T cells can be supported by type I and type II interferons (IFN). To characterize the role of type I interferons further we tested the role of recombinant IFN-alpha and IFN-beta on the induction of a weak immune response, against a low immunogenic tumor, which has been shown to be increased by IFN. Both type I interferons IFN-alpha and IFN-beta were able to support the differentiation of cytolytic T lymphocytes (CTL). In case of IFN-alpha no correlation with the antiviral activity could be seen by comparison of IFN-alpha1 and IFN-alpha4. The maximal in vitro effects were achieved with very low concentrations in the range of 1-100 IU/ml. IFN-alpha showed the strongest effects, if added in the early phase of the mixed leukocyte culture, whereas IFN-beta was most effective when given at the last day the culture. In combination, both IFNs gave additional/synergistic effects, whereby addition of IFN-alpha at day 0 and IFN-beta at day 4 led to maximal specific CTL responses. In vivo augmentation of the anti-tumor immune response by both types of IFNs supported the in vitro findings and also the synergistic effect of both types of IFNs could be demonstrated. Therefore we propose that IFN-alpha is relevant in the induction of CTL responses, i.e., the conversion of precursor T cell into mature cells and growth promotion whereby IFN-beta might trigger the lytic machinery of the cells and promote differentiation. This synergistic efficacy is also operative in tumor rejection.

Published
1995
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3. 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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4. Tumour-Specific CTL response requiring interactions of four different cell types and recognition of MHC class I and class II restricted tumour antigens

Author

Volker Schirrmacher, Brigitte Gückel, Paul von Hoegen, and Hansjörg Schild

Subjects
CD4-Positive T-Lymphocytes, 0301 basic medicine, CD74, Receptors, Antigen, T-Cell, alpha-beta, Immunology, CD1, Antigen-Presenting Cells, chemical and pharmacologic phenomena, Human leukocyte antigen, Biology, Major histocompatibility complex, T-Lymphocytes, Regulatory, Major Histocompatibility Complex, Mice, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Antigens, Neoplasm, MHC class I, Tumor Cells, Cultured, Animals, Immunology and Allergy, Antigen processing, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Antibodies, Monoclonal, T-Lymphocytes, Helper-Inducer, Cell Biology, MHC restriction, Mice, Inbred C57BL, CTL, 030104 developmental biology, Mice, Inbred DBA, biology.protein, T-Lymphocytes, Cytotoxic, 030215 immunology
Abstract

This study demonstrates that a syngeneic specific cytotoxic T lymphocyte (CTL) response to a class I major histocompatibility complex (MHC) positive tumour requires dual processing and recognition of tumour antigens. One type of antigen is processed and expressed in association with class I MHC at the surface of intact tumour cells. It is recognized by CD8 alpha, beta TCR CTL in vitro and by protective immune T cells in vivo and thus functions as a tumour-associated transplantation antigen (TATA). The other type of antigen is processed and expressed by distinct host APC in association with class II MHC. This is recognized by immune CD4 T cells which function as essential helper cells in the generation of the CD8 CTL response. These conclusions are supported by cell depletion and reconstitution experiments as well as by blocking experiments with monoclonal antibodies using the highly metastatic class II negative murine lymphoma ESb as a model system. The existence of two types of cognate T cell responses in a syngeneic anti-tumour response was directly proved by the establishment of two types of tumour specific T cell lines which required as co-stimulator either MHC class II positive APC or IL-2. In suboptimal mixed lymphocyte tumour cell cultures either of these co-stimulator functions was found to be limiting the overall anti-tumour CTL response. The generation of the tumour specific CTL response could be blocked by monoclonal antibodies against all the molecules involved in the cognate interactions (i.e. class I MHC, CD8, class II MHC, CD4 and TCR) but not by anti-CD2 or anti-IgG. The strict requirement for helper cells and APC could be bypassed by the addition of recombinant IL-2 but optimal triggering of CD8 CTL-precursor required viable tumour stimulator cells. This well characterized in vitro assay may be useful (i) for monitoring the immune status of CD4 and CD8 immune T cells separately, for instance of tumour bearing and/or treated animals and (ii) for the development and testing of potent tumour cell vaccines with T cell stimulatory and/or co-stimulatory activities.

Published
1993
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5. Synthetic biomimetic supra molecular Biovector (SMBV) particles for nasal vaccine delivery

Author

Paul von Hoegen

Subjects
Cellular immunity, Vaccines, Vaccines, Synthetic, medicine.medical_treatment, Pharmaceutical Science, Biology, Drug Delivery Systems, Membrane protein, Nasal spray, Antigen, Adjuvants, Immunologic, Influenza Vaccines, Humoral immunity, Immunology, medicine, biology.protein, Animals, Cytokines, Humans, Antibody, Drug carrier, Adjuvant, Administration, Intranasal
Abstract

For the optimal delivery of antigens to mucosal tissues, especially as nasal sprays, protein antigen alone is often not sufficient. A clear need for nasal delivery systems has therefore evolved, especially for Influenza A vaccines. Such technologies will be even more essential for new modern vaccines based on recombinant antigens. Here we describe synthetic biomimetic supra molecular Biovector™ (SMBV™) which have proven in preclinical and clinical evaluation to be suitable candidates for the delivery of nasal vaccines. They also demonstrate the potential to work with multiple antigens and furthermore allow combination with adjuvants. These Biovectors can associate with internal or lipid layer membrane proteins and peptides due to their charged polysaccharide core. The mimicry with viruses is also provided through their size of 60–80 nm, which allows sterilization by filtration. This makes them an ideal tool for the development of modern nasal vaccines, as they have shown to be able to induce the desired types of humoral immunity (serosal and mucosal immunity, IgA and IgG antibodies) as well as cellular immunity (CD4 and CD8 responses).

Published
2001

6. Deficiency in T cell responses of human fetal lymph node cells: a lack of accessory cells

Author

Sujata Sarin, Paul von Hoegen, and John F Krowka

Subjects
0301 basic medicine, Adult, Antigens, Differentiation, T-Lymphocyte, T cell, T-Lymphocytes, Immunology, Antigen-Presenting Cells, Spleen, Thymus Gland, Biology, Lymphocyte Activation, Immunophenotyping, 03 medical and health sciences, Embryonic and Fetal Development, 0302 clinical medicine, Immune system, Antigens, CD, medicine, Lymph node stromal cell, Immunology and Allergy, Mesenteric lymph nodes, Humans, Lectins, C-Type, Mesentery, Antigen-presenting cell, Lymph node, Cell Biology, Fetal Blood, Molecular biology, 030104 developmental biology, medicine.anatomical_structure, Lymphatic system, Lymph Nodes, Immunocompetence, 030215 immunology
Abstract

Lymph node and spleen cells of human foetuses from the 18th to the 24th week of gestation were analysed with regard to their phenotypes and their functional capacities. Fetal mesenteric lymph nodes contain high percentages of CD45RA+ T cells and few B cells and monocytes, whereas the fetal spleen is comprised of equal numbers of T and B cells as well as monocytes/macrophages. Functional analysis of lymph node T cells revealed a lack of proliferative response to PHA or CD3 specific mAb, despite induction of expression of the activation marker CD69. Proliferation of LN cells and thymocytes was observed upon addition of exogenous IL-2. An allogeneic EBV transformed tumour cell line, known to be an effective antigen presenting cell, could induce proliferation of LN cells without exogenous IL-2 and fetal spleen cells could proliferate in response to all stimuli tested without additional IL-2. Splenic non-T cells could restore the proliferation of lymph node cells as efficiently as IL-2 or the EBV transformed B cell line. Separated B cells were more effective than plastic adherent cells on a per cell basis. Naivity of the fetal immune system is therefore not only reflected by the expression of markers representative for naive lymphocytes but can also be due to the absence of potential accessory cells in the different lymphoid organs.

Published
1995

7. Antibody 12-15 cross-reacts with mouse Feγ receptors andCD2: study of thymus expression, genetic polymorphism and biosynthesis of the CD2 protein

Author

Elke Lang, Volker Schirrmacher, Paul von Hoegen, Ulrike Kohl, and Peter Altevogt

Subjects
Antigens, Differentiation, T-Lymphocyte, Immunology, CD2 Antigens, Fc receptor, Receptors, Fc, Thymus Gland, Cross Reactions, Immunofluorescence, Binding, Competitive, Epitope, Mice, Antigen, medicine, Animals, Immunology and Allergy, Cytotoxic T cell, Receptors, Immunologic, Mice, Inbred BALB C, Polymorphism, Genetic, biology, medicine.diagnostic_test, Receptors, IgG, Antibodies, Monoclonal, Membrane Proteins, T lymphocyte, Antigens, Differentiation, Molecular biology, Thymocyte, Mice, Inbred DBA, biology.protein, Antibody, T-Lymphocytes, Cytotoxic
Abstract

Previously we described a monoclonal antibody (mAb 12-15) that reacted with murine Fc receptor proteins (beta 1, beta 2 and alpha) and an undefined molecule of 37 kDa (beta 3) on certain types of cells. Here we present serological and biochemical evidence that the beta 3 chain is expressed on mouse thymocytes and that it is identical to the CD2 antigen. By immunofluorescence staining and cytofluorographic analysis greater than 95% of thymocytes were positive. Brightly staining cells coincided with cortisone-resistant thymocytes suggesting that mature thymocytes expressed higher levels of the antigen. Biosynthetic labeling of DBA/2 thymocytes with [35S]methionine showed that the size of the CD2 precursor molecule was 43 kDa which was processed to approximately 55-65 kDa in the mature molecule. mAb 12-15 was also reactive with the tunicamycin-treated form of the CD2 antigen suggesting that the cross-reactive epitope was of protein nature. Comparison of different mouse strains indicated that two molecular forms of CD2 exist. On BALB/c thymocytes, the relative mass of the native molecule was approximately 60-70 kDa (CD2.1) and slightly larger than in DBA/2 (CD2.2). Following endoglycosidase F treatment both proteins still showed a slight difference in electrophoretic mobility. Several inbred mouse strains were analyzed for expression of CD2 forms. When mAb 12-15 was used in cytotoxic T lymphocyte inhibition experiments using specific CTL and tumor target cells it was found that the antibody could specifically inhibit CTL-mediated lysis presumably by interfering with CD2 function.

Published
1989
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8. Modification of tumor cells by a low dose of Newcastle disease virus

Author

Paul von Hoegen, Volker Schirrmacher, and Hansjörg Schild

Subjects
Antigens, Differentiation, T-Lymphocyte, Cytotoxicity, Immunologic, Interleukin 2, Cancer Research, Time Factors, Lymphoma, T-Lymphocytes, viruses, animal diseases, T cell, Lymphocyte Cooperation, Immunology, Newcastle disease virus, Mice, Nude, Biology, Epitope, Epitopes, Mice, Interleukin 21, Immune system, Antigen, medicine, Animals, Immunology and Allergy, Cytotoxic T cell, Viral Vaccines, biochemical phenomena, metabolism, and nutrition, Cell Transformation, Viral, Phenotype, medicine.anatomical_structure, Oncology, Mice, Inbred DBA, Interleukin-2, CD8, medicine.drug
Abstract

Augmented tumor-specific T cell responses were observed against the high metastatic murine lymphoma variant ESb when using as immunogen ESb tumor cells that had been modified by infection with a low dose of Newcastle disease virus (NDV). Such virus-modified inactivated tumor cells (ESb-NDV) were potent tumor vaccines when applied postoperatively for active specific immunotherapy of ESb metastases. We demonstrate here that immune spleen cells from mice immunized with ESb-NDV contain enhanced immune capacity in both the CD4+, CD8- and the CD4-, CD8+ T cell compartments to mount a secondary-tumor-specific cytotoxic T cell response in comparison with immune cells from mice immunized with ESb. ESb-NDV immune CD4+, CD8- helper T cells also produced more interleukin 2 after antigen stimulation than the corresponding ESb immune cells. There was no participation of either CD4+ or CD8+ virus-specific cells in the augmented response. The specificity of the T cells for the tumor-associated antigen remained unchanged. Thus, there is the paradox that the virus-mediated augmentation of the tumor-specific T cell response in this system involves increased T helper activity but does not involve the recognition of viral epitopes as potential new helper determinants.

Published
1989
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9. New antigens presented on tumor cells can cause immune rejection without influencing the frequency of tumor-specific cytolytic T cells

Author

Volker Schirrmacher, Peter Altevogt, and Paul von Hoegen

Subjects
Cytotoxicity, Immunologic, Graft Rejection, Immunology, Mast-Cell Sarcoma, chemical and pharmacologic phenomena, Biology, Mice, Immune system, Antigen, Antigens, Neoplasm, Minor histocompatibility antigen, Cytotoxic T cell, Animals, Transplantation, Homologous, Leukemia L5178, Pan-T antigens, Leukemia, Experimental, Acquired immune system, Transplantation, CTL, Kinetics, Mice, Inbred DBA, Antigens, Surface, Female, Neoplasm Transplantation, T-Lymphocytes, Cytotoxic
Abstract

The specific immune response against syngeneic tumors by T cells is dependent on the existence of tumor-associated transplantation antigens (TATA). In the case of the chemically induced DBA/2-derived lymphoma Eb and its highly metastatic variant ESb the immunogenicity of these antigens is not sufficient to prevent tumor growth. Therefore we tested in two systems the influence of additional antigens as possible helper determinants for the generation of tumor-specific immune responses. In the Eb tumor system additional antigens were induced by mutagenization. The frequency of cytotoxic T lymphocytes (CTL) in response to mutagenized Eb cells was higher than that in response to untreated Eb cells. Fine specificity analysis revealed there there was no increase in the CTL response against the original TATA, but an activation of additional CTL clones responding to mutagen-induced antigens. In the ESb tumor system we tested the effect of additional recognition of minor histocompatibility antigens on the frequency of TATA-specific CTL. Transplantation of ESb tumor cells into B10.D2 mice, which are H-2-identical but differ in minor antigens, results in strong tumor rejection responses. In a limiting dilution mixed-leukocyte-tumor microculture system it was found that the minor antigens are recognized at the clonal level as independent antigens. The overall frequency of anti-tumor CTL in ESb-immunized B10.D2 mice was about 1 3000 . Among these, the frequency of TATA-specific CTL was 1 16,709 and thus not significantly different from that of syngeneic DBA/2 mice. Thus neither minor antigens nor mutagen-induced antigens acted in the Eb/ESb tumor system as helper determinants and did not increase the frequency of tumor-specific CTLs.

Published
1987

10. CD4+ helper T cells are required for resistance to a highly metastatic murine tumor

Author

Bruno Kyewski, Hansjörg Schild, Volker Schirrmacher, and Paul von Hoegen

Subjects
Graft Rejection, Lymphoma, Immunology, Lymphocyte Cooperation, Mice, Inbred Strains, In Vitro Techniques, Interleukin 21, Mice, medicine, Immunology and Allergy, Cytotoxic T cell, Animals, IL-2 receptor, Neoplasm Metastasis, Antigen-presenting cell, Cells, Cultured, Interleukin 3, CD40, biology, Neoplasms, Experimental, T-Lymphocytes, Helper-Inducer, medicine.disease, Transplant rejection, biology.protein, Interleukin 12, Cancer research, Interleukin-2, Neoplasm Transplantation, T-Lymphocytes, Cytotoxic
Abstract

A role of CD4+ T helper cells in induction of tumor transplant rejection leading to complete regression of a highly metastatic DBA/2 mouse lymphoma was analyzed. Using an anti-CD4 monoclonal antibody (GK1.5) which eliminates T helper cells in vivo and in vitro, we found that CD4+ cells are required for tumor resistance in syngeneic DBA/2 mice or allogeneic but major histocompatibility complex-identical B10.D2 mice. In contrast, in allogeneic C57BL/6 mice tumor rejection was independent of CD4+ cells. An analogous requirement for immune CD4+ cells for in vitro induction of CD8+ tumor-specific cytotoxic T cells was found in these respective strains. The requirement for immune CD4+ cells in vitro could be replaced by recombinant interleukin 2. These results demonstrate a role of CD4+ regulatory T cells and T-T cell cooperation in the induction of anti-tumor immunity and tumor rejection, and point to possible therapeutic interventions in the afferent phase of anti-tumor immune responses.

Published
1987

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