Targeted stealth adenoviruses for the cell-specific delivery of cancer immunotherapies
Sheena N. Smith, Seraina Jans, Dominik Brücher, Birgit Dreier, Markus Schmid, & Andreas Plückthun
Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland
Recently, we described an adenoviral delivery system that allows for specific targeting of adenovirus serotype 5 (Ad5) to discrete cell populations through the use of interchangeable designed bispecific designed ankyrin repeat protein (DARPin) adapters. In contrast to other strategies utilizing Ad5 for its oncolytic properties, we have engineered Ad5 into a non-oncolytic, ‘shielded’ delivery vehicle for therapeutic genes due to its large packaging capacity (up to 36 Kb) and the feature that the viral DNA remains episomal rather than randomly integrating into host chromosomes, providing an additional safety margin for clinical applications. Here, we propose the use of this delivery system for two unique applications in cancer immunotherapies. In the first application, adenoviral particles are directed to selectively transduce tumor cells or tumor stromal cells with the genes encoding cocktails of secreted monoclonal antibodies (mAb)- and/or other protein-based therapeutics (e.g. checkpoint blockers, cytokines). The transduced subpopulation of cells then serves as a ‘biofactory,’ secreting therapeutics that act in a paracrine fashion within the tumor microenvironment to promote the activation of tumor-infiltrating lymphocytes (TILs) locally, thus limiting toxicity to peripheral tissues. In a second application, bispecific adaptors have been generated that mediate viral delivery to the surface of discrete T cell populations (e.g. CD4+, CD8+) as potential in vivo delivery vehicles for cell-mediated immunotherapies. We propose that this approach could provide a less cumbersome alternative to ex vivo modification of T cells with tumor-specific T cell receptors (TCRs) or chimeric antigen receptors (CARs) for autologous transfer.