A fundamental goal of cancer drug delivery is to achieve sufficient levels within the tumour without leading to high systemic concentrations that might cause off-target toxicities. In situ production of protein-based therapeutics by tumour cells provides an attractive alternative to treatment with repeated high bolus injections, as secretion by the tumour itself could provide high local
concentrations that act in a paracrine fashion over an extended duration. For this purpose, we have developed a non-oncolytic adenoviral delivery system that allows for targeting of Ad5 to discrete cell types by redirecting viral tropism to cell surface biomarkers through the use of interchangeable adapters. Furthermore, we recently described the engineering of a protein-based ‘shield’ that is coated on the Ad5 capsid, which, together
with the retargeting adapters, allows for improved tumour specificity
and prevention of viral clearance. To test this delivery
strategy in vivo, SCID-beige mice bearing orthotopic BT474
xenografts were treated with three doses of either a cancerspecific,
non-replicative Ad5 that encodes a secreted anti-HER2
antibody, trastuzumab, in its genome, or with the protein therapeutic
itself (Herceptin®). We have employed state-of-the-art
whole tumour clearing and imaging with confocal microscopy at
high spatial resolution in 3D to assess biodistribution, and large
volumetric imaging has revealed that the secreted therapeutic
diffuses significantly throughout the tumour leading to a therapeutic
effect and delayed tumour outgrowth. Moreover, the systemic
concentration of antibody is significantly reduced with viral
delivery, suggesting that paracrine delivery may be a promising
strategy for delivery of biologics with narrow therapeutic indices
