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