Project

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Paracrine delivery of therapeutic biologicals: developing a new technology for personalized cancer immunotherapy

Applicant Plückthun Andreas
Number 170929
Funding scheme Sinergia
Research institution Biochemisches Institut Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Interdisciplinary
Start/End 01.01.2017 - 31.12.2020
Approved amount 2'407'860.00
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All Disciplines (4)

Discipline
Interdisciplinary
Biochemistry
Experimental Cancer Research
Molecular Biology

Keywords (8)

immune checkpoint modulators; immuno-oncology; therapeutic antibodies; tumor therapy; protein engineering; viral delivery; virus engineering; adenovirus

Lay Summary (German)

Lead
Krebs bleibt eine der grossen globalen Herausforderungen für die menschliche Gesundheit. Die Immuntherapie hat bedeutende Fortschritte erzielt, aber leider nur für eine kleine Zahl von Patienten. In diesem Projekt wird eine völlig neuartige Technologie entwickelt werden, in dem die Therapeutika im betroffenen Gewebe selbst hergestellt werden und durch kurze Diffusion zu den erkrankten Zellen gelangen.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Mit den Methoden des modernen Protein Engineering werden Adenoviren konstruiert, die keine virale DNA mehr enthalten und deswegen sich nicht vermehren können. Sie sind so umgebaut, dass sie nur die gewünschten Zellen in der Nachbarschaft eines Tumors infizieren können und sie werden für das Immunsystem unsichtbar gemacht. Diese Partikel enthalten die DNA für therapeutische Proteine, die am Ort des Geschehens produziert und sekretiert werden und die kranken Zellen erreichen. Insbesondere können auf diese Art hochwirksame Medikamente zum Einsatz kommen, die an anderen Stellen des Körpers Nebenwirkungen hervorrufen würden. Dazu gehören unter anderem therapeutische Antikörper, Faktoren, die das Immunsystem stimulieren, Cytokine sowie Faktoren, die die Blutversorgung des Tumors beeinflussen.

 

Das Projekt wird demnach eine fundamental neue Technologie entwickeln durch die Zusammenarbeit von Protein- und Virus-Engineering, der Untersuchung der viralen Infektionsmechanismen, und des Wirkmechanismus der Immunantwort auf einen Tumor. Auf diese Art soll das enorme Potential hochaktiver biologischer Therapeutika erheblich besser nutzbar werden.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Das Projekt beschäftigt sich mit Grundlagenforschung. Im Verlauf des Projekts werden aber Technologien und Konzepte entwickelt werden, die in präklinischen Mausmodellen getestet werden mit der Vision, davon die besten ultimativ in klinische Praxis übertragen zu können.

Direct link to Lay Summary Last update: 23.12.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control
Schmid Markus, Ernst Patrick, Honegger Annemarie, Suomalainen Maarit, Zimmermann Martina, Braun Lukas, Stauffer Sarah, Thom Cristian, Dreier Birgit, Eibauer Matthias, Kipar Anja, Vogel Viola, Greber Urs F., Medalia Ohad, Plückthun Andreas (2018), Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control, in Nature Communications, 9(1), 450-450.
Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor
Stichling Nicole, Suomalainen Maarit, Flatt Justin W., Schmid Markus, Pacesa Martin, Hemmi Silvio, Jungraithmayr Wolfgang, Maler Mareike D., Freudenberg Marina A., Plückthun Andreas, May Tobias, Köster Mario, Fejer György, Greber Urs F. (2018), Lung macrophage scavenger receptor SR-A6 (MARCO) is an adenovirus type-specific virus entry receptor, in PLOS Pathogens, 14(3), e1006914-e1006914.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Didier Lardinois, Universitätssptial Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Ohad Medalia, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Iwan Schaap, Heriot Watt University Edinburgh Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Carmen San Martin, Centro Nacional de Biotecnologia (CNB-CSIC), Madrid Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
PD Dr. Silvio Hemmi, University of Zurich, IMLS Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Louis M. Weiner, Georgetown University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Albert Heck, University of Utrecht Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Pedro de Pablo, Universidad Autónoma de Madrid Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
PEGS Europe Talk given at a conference Using protein engineering to make therapeutics in situ 12.11.2018 Lissabon, Portugal Plückthun Andreas;
13th International Adenovirus Meeting Talk given at a conference Using structural biology for designing a targeting adapter and a detargeting shield for human adenovirus 5 24.09.2018 San José Vista Hermosa, Mexico Plückthun Andreas;
Antibody Engineering & Therapeutics Europe Talk given at a conference Paracrine Delivery: Therapeutic biomolecules produced in situ 05.06.2018 Amsterdam, Netherlands Plückthun Andreas;
BaseLaunch Talk given at a conference Novel technologies for accessing cutting edge therapeutid concepts 24.04.2018 Basel, Switzerland Plückthun Andreas;
LSZ-Impact: Translational Medicine Conference 2018 Talk given at a conference Novel technologies create new molecules for accessing cutting-edge therapeutic concepts 22.01.2018 Zürich, Switzerland Plückthun Andreas;


Associated projects

Number Title Start Funding scheme
188576 Genome-wide CRISPR screen to identify genes involved in T cell dysfunction and novel targets for cancer immunotherapy 01.03.2020 Project funding (Div. I-III)
192689 Next generation of protein binders and degraders by combining computational design and evolution 01.04.2020 Project funding (Div. I-III)
182334 G protein-coupled receptors: from evolving stable receptors to structure and function 01.04.2019 Project funding (Div. I-III)
189780 Multidimensional immune profiling of single cells using mass cytometry 01.01.2020 R'EQUIP
183382 A state-of-the-art detector for cryo-electron microscopy 01.06.2019 R'EQUIP
65344 Antibody engineering: Improving folding and stability by rationalengineering and evolutionary techniques 01.10.2001 Project funding (Div. I-III)

Abstract

Cancer continues to be a major global health problem. Immunotherapy has generated unprecedented clinical successes with several important therapeutic breakthroughs occurring within the last years. Still, therapeutic benefits have remained restricted to only a limited number of patients.This interdisciplinary project will develop a completely novel technology: the first-in-class platform for the paracrine delivery of therapeutic proteins in targeted tissues. Using advanced protein engineering approaches, novel adenoviral vectors will be developed that overcome several key challenges in conventional gene therapy, such as shielding from the immune system, targeting infectivity to only the cell types of choice, and removal of viral genes to prevent viral replication and genome integration. These targeted, ‘stealth’ viruses will be designed to infect cells in a tumor and its microenvironment to locally produce and secrete therapeutic agents in a paracrine manner, offering a profound advantage for administration of agents that are highly effective but problematic on a systemic level due to toxicities, and/or agents that require continuously high local concentrations for efficacy. Agents to be investigated include therapeutic antibodies for the blockade of inhibitory receptors/metabolites on immune cells, quenching of stromal growth factors, immune checkpoint modulators, cytokines for the recruitment and activation of immune effector populations, and/or reshaping of the tumor vasculature. The objectives of this collaborative project include the engineering of both ‘stealth’ viral vectors and of therapeutic payloads, the detailed analysis of the subcellular infection and transgene expression, the mechanistic evaluation of the performance of payloads in cellular, spheroid and tumor biopsy models, and finally the performance of the concept in immunocompetent mouse models and tumors from patients. The project will thus develop a fundamental technology, guided by the basic science of protein and virus engineering and the mechanistic understanding of therapeutic proteins, which can be eventually applied to individualize therapy by delivering complex, designer combinations of biologics. It will provide a novel strategy to achieve high and continuous intra-tumoral activity of biologics with an improved therapeutic index, and thereby finally harness the enormous potential of biologically active therapeutics that are currently limited by high systemic toxicities.To achieve this ambitious goal we have assembled a consortium representing leading scientists in each of the key areas essential for the development of this endeavor: protein engineering (Andreas Plückthun), adenovirus biology (Urs Greber) and cancer immunology (Alfred Zippelius). Only the combined expertise of these laboratories will make it possible to tackle such an ambitious project.At the end of this project and after successful proof of principle in animal experiments, it is foreseen that this technology will be translated to the clinic making it available to patients and perhaps ultimately commercialized by industry. The project will also have a very important teaching component, especially for the PhD students and postdocs directly involved, through shared group meetings and a "mutual teaching" of the various technologies. Thus, the participating students will be well-versed in a variety of novel approaches in biotechnology and extremely well prepared for the job market in the field of biomedicine.
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