Description

Introduction and aim:

The rational underlying therapeutic cancer vaccines is the stimulation of the patient’s own immune system using tumor antigen to control and eradicate oncogenesis. In the last decade, new inside especially regarding immunogenetic neo-antigens (and the choice of antigens in general) had been made helping to improve vaccination protocols, leading to a revival of the whole field.

Our group is specialized in protein engineering and developed recently a gene delivery platform, based on the Human Adenovirus 5 (HAdV5). It features 1) generic and specific gene delivery to tumor markers1,2, 2) reduction of viral clearance3 and 3) an increased packaging capacity of up to 37 kb (HC-HAdV5)4. Implementation of these three hallmarks allows the design of a patient-tailored vector that drives the in situ expression of a synergistic cocktail of therapeutics, precisely targeting the specific vulnerabilities of the patient’s tumor.

In context of tumor vaccination we offer the following project

·         Design of HAdV5 vectors for vaccination approaches in tumor immunology: encoding antigens and immunostimulatory payloads (e.g. checkpoint blockade, cytokines)

·         Directed vaccination approach: Targeting professional antigen presenting cells for payload delivery: Adapter for specific targeting of e.g. Dendritic cells

During this thesis you will deepen your knowledge in the techniques of cloning of high capacity vectors, protein expression and purification, production of adenoviral particles, cellular analysis by flow cytometry. Also, you are introduced to working under sterile conditions in cell culture (working with immune cell lines and primary cells) and BSL2.

Requirements: student has gathered technical experiences in previous lab projects (working with proteins and cloning) and is self-organized. In the best case has a solid understanding of current immune therapies

 

References:

1              Dreier, B. et al. Her2-specific multivalent adapters confer designed tropism to adenovirus for gene targeting. J Mol Biol 405, 410-426, doi:10.1016/j.jmb.2010.10.040 (2011).

2              Dreier, B. et al. Development of a generic adenovirus delivery system based on structure-guided design of bispecific trimeric DARPin adapters. Proc Natl Acad Sci U S A 110, E869-877, doi:10.1073/pnas.1213653110 (2013).

3              Schmid, M. et al. Adenoviral vector with shield and adapter increases tumor specificity and escapes liver and immune control. Nat Commun 9, 450, doi:10.1038/s41467-017-02707-6 (2018).

4              Brücher, D. et al. iMATCH – an integrated modular assembly-system for therapeutic combination high-capacity adenovirus gene therapy. Molecular Therapy – Methods & Clinical Development, doi:10.1016/j.omtm.2021.01.002 (2021).