Targeted Stealth Adenovirus as a ‘Trojan Horse’ for Delivery of Cancer Therapies

Monday, June 18, 2018 -
2:00pm to 3:00pm
FUNG Auditorium
Sheena Smith

Postdoctoral Fellow at the University of Zürich

Laboratory of Andreas Plückthun

Targeted Stealth Adenovirus as a ‘Trojan Horse’ for Delivery of Cancer Therapies

Abstract: 

The last decade has shown immense innovation in the discovery and implementation of new cancer treatment modalities, including immunotherapy, combination therapies of biologics and cell- and gene-based approaches. Despite the potential of these strategies, maintenance of adequate therapeutic windows and cost-effectiveness limit their scope in the clinic. To address this, we have developed a non-oncolytic adenoviral delivery system that allows for specific targeting of Ad5 to discrete cell types by redirecting viral tropism to cell surface biomarkers through the use of interchangeable bispecific designed ankyrin repeat protein (DARPin) adapters[1]. Furthermore, we have engineered a protein-based ‘shield’ that is coated on the Ad5 capsid, which, together with the retargeting adapters, allows for improved tumor specificity and prevention of liver and immune-based clearance mechanisms[2]. Here, we will describe several applications of this platform for cancer drug delivery. In our primary application, Ad5 particles are directed to transduce tumor or stromal cells with genes encoding cocktails of secreted monoclonal antibodies and/or other protein-based therapeutics. The transduced subpopulation of cells then serves as a ‘biofactory,’ secreting drugs that act in a paracrine fashion within the tumor microenvironment to collectively target multiple oncogenic pathways, increase anti-tumor immunity, and/or enhance tumor perfusion. We propose that this strategy could allow for high local levels of efficacious therapeutic cocktails reducing the development of drug resistance as well as provide a safer alternative to systemic administration. In addition, we will describe the development of this platform for further applications in delivery of cell-based therapies, including chimeric antigen receptors to T cells, CRISPR/Cas9-based gene editing to mutated tissues, and cancer vaccine cocktails to dendritic cells. We propose this platform could increase the safety profiles of gene-modified cells and the cost-effectiveness of GMP production of cell-based therapeutics.

 


[1]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).

[2]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).

Bio: 

Sheena Smith is a postdoctoral fellow at the University of Zürich in the laboratory of Andreas Plückthun. Her research focuses on the development and implementation of protein engineering strategies for the generation and delivery of cancer therapeutics. Sheena received her PhD in 2014 from the University of Illinois at Urbana-Champaign where her research focused on the engineering of T cell receptors as candidates for targeted immunotherapies. Notably, she developed a semi-rational design platform that allows T cell receptors to be engineered entirely in vitro against cancer biomarkers.