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Vaccine and immunotherapy induced CD8+ T cell responses against auto-, neo- and foreign antigens

English title Vaccine and immunotherapy induced CD8+ T cell responses against auto-, neo- and foreign antigens
Applicant Flatz Lukas
Number 157448
Funding scheme SNSF Professorships
Research institution Institut für Immunbiologie Kantonsspital St. Gallen
Institution of higher education Cantonal hospital of St.Gallen - KSPSG
Main discipline Dermatology
Start/End 01.01.2016 - 31.12.2019
Approved amount 1'397'323.00
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All Disciplines (3)

Discipline
Dermatology
Experimental Cancer Research
Immunology, Immunopathology

Keywords (5)

CTLA4/PD1 blockade; Vaccine; T cells; Immunotherapy; Melanoma

Lay Summary (German)

Lead
Im Gegensatz zu vielen Infektionskrankheiten kann Krebs ausser wenigen Ausnahmen bislang nicht mittels Impfung verhütet oder bekämpft werden. Ein Grund dafür ist, dass zur Bekämpfung des Melanoms eine ausserordentlich kraftvolle Armee von Killer T-Zellen notwendig wäre : Klassische Impfungen sind dazu aber kaum in der Lage und schützen vor allem durch Antikörper. Wir haben daher eine Strategie entwickelt, um durch neuartige Impfvektoren, die auf Viren basieren, solche spezifischen Killer T-Zellen zu aktivieren.
Lay summary
Seit vielen Jahrzehnten ist bekannt, dass das Lymphozytäre Choriomeningitis Virus ( LCMV ) Killer T-Zellen aussergewöhnlich gut stimuliert. Wir haben daher eine Strategie entwickelt, um LCMV ungefährlich zu machen und gleichzeitig Bestandteile von Krebszellen in dieses einzusetzen. Erste Daten zeigen, dass wenn ein solches verändertes und ungefährliches Virus an Mäuse verabreicht wird, übertrug sich die Fähigkeit zur Killer T Zell
Stimulation auf den Bestandteil des Tumors und übertraf in Zahl und Qualität jene der bisher bekannten
Impfstoff-Träger. In dem vorgeschlagenen Projekt studieren wir im Detail gegen welche Bestandteile des Tumors wir impfen müssen und welche Mechanismen es ermöglichen, dass die Killer T-Zellen den Tumor zerstören. Am Anfang konzentrieren wir uns dabei auf die Bestandteile, die von Melanozyten produziert werden. Melanozyten sind die normalen Zellen in der Haut, die uns vor dem Sonnenlicht schützen und als Melanom bezeichnet werden, wenn sie bösartig entarten. Eine Zerstörung aller Zellen, die Komponenten von Melanozyten enthalten, wird neben Melanomzellen auch einen Teil von normalen Melanozyten töten. Deshalb konstruieren wir parallel auch Impfstoffe, die nur solche Killer T-Zellen stimulieren, die spezifisch gegen Melanombestandteile gerichtet sind. Dabei wird die genetische Information des Tumors entschlüsselt und mit normalen Melanozyten verglichen.
In den neuartigen Impfstoff bauen wir dann nur die Bestandteile ein, die nötig sind, um das Melanom zu
bekämpfen. Ein erfolgreicher Abschluss der vorgeschlagenen Experimente wird uns erlauben, klinische Studien in Patienten zu planen.
Direct link to Lay Summary Last update: 24.12.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Antibodies as biomarker candidates for response and survival to checkpoint inhibitors in melanoma patients
Fässler Mirjam, Diem Stefan, Mangana Joanna, Hasan Ali Omar, Berner Fiamma, Bomze David, Ring Sandra, Niederer Rebekka, del Carmen Gil Cruz Cristina, Pérez Shibayama Christian Ivan, Krolik Michal, Siano Marco, Joerger Markus, Recher Mike, Risch Lorenz, Güsewell Sabine, Risch Martin, Speiser Daniel E., Ludewig Burkhard, Levesque Mitchell P., Dummer Reinhard, Flatz Lukas (2019), Antibodies as biomarker candidates for response and survival to checkpoint inhibitors in melanoma patients, in Journal for ImmunoTherapy of Cancer, 7(1), 50-50.
Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy
Gil-Cruz Cristina, Perez-Shibayama Christian, De Martin Angelina, Ronchi Francesca, van der Borght Katrien, Niederer Rebekka, Onder Lucas, Lütge Mechthild, Novkovic Mario, Nindl Veronika, Ramos Gustavo, Arnoldini Markus, Slack Emma M.C., Boivin-Jahns Valérie, Jahns Roland, Wyss Madeleine, Mooser Catherine, Lambrecht Bart N., Maeder Micha T., Rickli Hans, Flatz Lukas, Eriksson Urs, Geuking Markus B., McCoy Kathy D., et al. (2019), Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy, in Science, 366(6467), 881-886.
Association Between Immune-Related Adverse Events During Anti–PD-1 Therapy and Tumor Mutational Burden
Bomze David, Hasan Ali Omar, Bate Andrew, Flatz Lukas (2019), Association Between Immune-Related Adverse Events During Anti–PD-1 Therapy and Tumor Mutational Burden, in JAMA Oncology, 5(11), 1633-1633.
BP180-specific IgG is associated with skin adverse events, therapy response and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors
Ali Omar Hasan, Bomze David, Ring Sandra, Berner Fiamma, Fässler Mirjam, Diem Stefan, Abdou Marie-Therese, Hammers Christoph, Emtenani Shirin, Braun Anne, Cozzio Antonio, Mani Bernhard, Jochum Wolfram, Schmidt Enno, Zillikens Detlef, Sadik Christian D., Flatz Lukas (2019), BP180-specific IgG is associated with skin adverse events, therapy response and overall survival in non-small cell lung cancer patients treated with checkpoint inhibitors, in Journal of the American Academy of Dermatology.
Association of Checkpoint Inhibitor–Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non–Small Cell Lung Cancer
Berner Fiamma, Bomze David, Diem Stefan, Ali Omar Hasan, Fässler Mirjam, Ring Sandra, Niederer Rebekka, Ackermann Christoph J., Baumgaertner Petra, Pikor Natalia, Cruz Cristina Gil, van de Veen Willem, Akdis Mübeccel, Nikolaev Sergey, Läubli Heinz, Zippelius Alfred, Hartmann Fabienne, Cheng Hung-Wei, Hönger Gideon, Recher Mike, Goldman Jonathan, Cozzio Antonio, Früh Martin, Neefjes Jacques, et al. (2019), Association of Checkpoint Inhibitor–Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non–Small Cell Lung Cancer, in JAMA Oncology, 5(7), 1043-1043.
Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma correspond to response and survival in nine patients treated with ipilimumab at the time of stage IV disease.
Diem Stefan, Hasan Ali Omar, Ackermann Christoph J, Bomze David, Koelzer Viktor H, Jochum Wolfram, Speiser Daniel E, Mertz Kirsten D, Flatz Lukas (2018), Tumor infiltrating lymphocytes in lymph node metastases of stage III melanoma correspond to response and survival in nine patients treated with ipilimumab at the time of stage IV disease., in Cancer immunology, immunotherapy : CII, 67(1), 39-45.
Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab.
Diem Stefan, Schmid Sabine, Krapf Mirjam, Flatz Lukas, Born Diana, Jochum Wolfram, Templeton Arnoud J, Früh Martin (2017), Neutrophil-to-Lymphocyte ratio (NLR) and Platelet-to-Lymphocyte ratio (PLR) as prognostic markers in patients with non-small cell lung cancer (NSCLC) treated with nivolumab., in Lung cancer (Amsterdam, Netherlands), 111, 176-181.
Interferon-γ-Driven iNOS: A Molecular Pathway to Terminal Shock in Arenavirus Hemorrhagic Fever.
Remy Melissa M, Sahin Mehmet, Flatz Lukas, Regen Tommy, Xu Lifen, Kreutzfeldt Mario, Fallet Benedict, Doras Camille, Rieger Toni, Bestmann Lukas, Hanisch Uwe-Karsten, Kaufmann Beat A, Merkler Doron, Pinschewer Daniel D (2017), Interferon-γ-Driven iNOS: A Molecular Pathway to Terminal Shock in Arenavirus Hemorrhagic Fever., in Cell host & microbe, 22(3), 354-365.
Spatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression.
Kalkavan Halime, Sharma Piyush, Kasper Stefan, Helfrich Iris, Pandyra Aleksandra A, Gassa Asmae, Virchow Isabel, Flatz Lukas, Brandenburg Tim, Namineni Sukumar, Heikenwalder Mathias, Höchst Bastian, Knolle Percy A, Wollmann Guido, von Laer Dorothee, Drexler Ingo, Rathbun Jessica, Cannon Paula M, Scheu Stefanie, Bauer Jens, Chauhan Jagat, Häussinger Dieter, Willimsky Gerald, Löhning Max, Schadendorf Dirk, Brandau Sven, Schuler Martin, Lang Philipp A, Lang Karl S (2017), Spatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression., in Nature communications, 8, 14447-14447.
Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer.
Lukas Flatz, Omar Hasan Ali, Stefan Diem, Wolfram Jochum, Katrin Kerl, Lars French, Eva Markert (2016), Characterization of nivolumab-associated skin reactions in patients with metastatic non-small cell lung cancer., in OncoImmunology, 5.
Generation of Lymphocytic Choriomeningitis Virus Based Vaccine Vectors.
Sandra Ring, Lukas Flatz (2016), Generation of Lymphocytic Choriomeningitis Virus Based Vaccine Vectors., in Sunil Thomas (ed.), Springer, Berlin, 351.
Pembrolizumab-triggered Uveitis: An Additional Surrogate Marker for Responders in Melanoma Immunotherapy?
Stefan Diem, Fabienne Keller, Reinhard Rüesch, Samia Maillard, Daniel Speiser, Reinhard Dummer, Marco Siano, Simone Goldinger, Ursula Urner-Bloch, Lukas Flatz (2016), Pembrolizumab-triggered Uveitis: An Additional Surrogate Marker for Responders in Melanoma Immunotherapy?, in Journal of Immunotherapy, 379.

Collaboration

Group / person Country
Types of collaboration
Nicholas Restifo / Luca Gattinoni (National Cancer Institute) United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Tobias Lenz Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof Stefan Kochanek (University of Ulm) Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof Dietmar Zehn (University of Lausanne) Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof Daniel Speiser (Ludwig Institute, University of Lausanne) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof Thomas Tüting (University of Bonn) Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Sergey Nikolaev France (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
NexGen Immunology Poster Antibody responses against skin antigens favor the development of adverse events during anti-PD1 therapy 10.02.2019 Rehovot / Weizmann Institute of Science, Israel Flatz Lukas;
JSCIA Talk given at a conference Mechanisms of checkpoint inhibitors mediated toxicity 16.11.2018 Nara, Japan Flatz Lukas;
iSCAR Talk given at a conference Checkpoint inhibitor mediated toxicity 09.11.2018 Shimane, Japan Flatz Lukas;
The International Cancer Immunotherapy Meeting (CIMT) Poster Virotherapy eradicates established melanoma by reprograming the tumor microenvironment 30.09.2018 NYC, United States of America Flatz Lukas;
Immunology Seminar Individual talk Skin toxicity of checkpoint inhibitors reveals shared antigens 19.09.2018 Leiden, Netherlands Flatz Lukas;
European Academy of Dermatology Annual Meeting Talk given at a conference Therapeutic targeting of the tumor microenvironment 12.09.2018 Paris, France Flatz Lukas;
Annual Meeting Swiss Society of Dermatology Talk given at a conference Toxicity of checkpoint inhibitors 30.08.2018 Lausanne, Switzerland Flatz Lukas;
International Investigative Dermatology Meeting Poster Autoantibodies against skin antigens favor the development of adverse events during anti-PD1 treatment 16.05.2018 Orlando, United States of America Flatz Lukas;
I3T Seminar series Individual talk Mechanisms of checkpoint inhibitor mediated toxicity 15.05.2018 Los Angeles, United States of America Flatz Lukas;
Immunologisches Seminar Individual talk Toxicity of checkpoint inhibitors reveals cancer antigens 29.03.2018 Rotterdam, Netherlands Flatz Lukas;
World Immune Regulatory Meeting (WIRM Davos) Poster Skin toxicity reveals cancer antigens 15.03.2018 Davos, Switzerland Flatz Lukas;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Puls SF DRS Immuntherapie gegen Krebs: Hoffnung oder Hype? Talk 30.10.2017 Zurich, Switzerland Flatz Lukas;
Kampf gegen Krebs mit dem eigenen Immunsystem Talk 09.03.2017 Triesen, Liechtenstein Flatz Lukas;


Associated projects

Number Title Start Funding scheme
164083 Flow cytometer for multiparametric analysis of rare cell populations 01.12.2015 R'EQUIP
187189 Vaccine and immunotherapy induced CD8+ T cell responses against auto-, neo- and foreign antigens 01.01.2020 SNSF Professorships

Abstract

The growing incidence of melanoma is an increasing threat, and effective treatment options for advanced forms of melanoma are scarce. Although recently approved targeted- and immunotherapies have shown objective beneficial effects in metastatic melanoma, in most cases the disease still relapses. In this project we are interested to understand the differences of immune responses against on one side vaccine vector intrinsic epitopes compared to tumor associated antigens consisting of classical melanoma antigens (melanA, gp100, trp2) and also recently characterized neoepitopes (emerged through de novo mutations in rapidly evolving tumor cells) - all provided by the same vaccine. These antigens will be presented in the context of the non-propagating recombinant lymphocytic choriomeningitis or adenovirus based vaccine vectors. For both of them we have well described Db restricted epitopes: FQPQNGQFI (NP396), FALSNAEDL (dbp43) respectively. In order to further increase the potency of the T cell immune response we will combine these with prime-boost immunizations using DNA plasmid, vaccinia virus, listeria vaccine vectors against the same antigens. Specifically we will pursue the following goals:1) To understand the topographic distribution and quality of simultaneously vaccine-induced T cells against auto-, neo- and foreign antigens in different immune compartments (skin, lymph nodes, blood, and spleen) in relation to the route of immunization over time.2) To characterize the behavior of anti-tumor and anti-virus T cells after tumor respectively virus challenge not only in the immune compartments but also in the tumor and its microenvironment using classical immunological assays and single cell real-time PCR.3) To unravel the effect of currently used immune activators (CTLA-4 and PD-1 blocking antibodies) on tumor and virus (EBV, CMV, Influenza) specific T cells in patients.A completion of these experiments may stimulate a discussion on thinking of a paradigm change in terms of prophylactic melanoma vaccination in high-risk individuals (Breslow >2mm and positive sentinel lymph node) instead of therapeutic immunotherapy in end stage melanoma.
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