The SHREAD gene therapy platform for paracrine delivery improves tumor localization and intratumoral effects of a clinical antibody

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 21; pp. 1 - 12
• Main Authors: Smith, Sheena N., Schubert, Rajib, Simic, Branko, Brücher, Dominik, Schmid, Markus, Kirk, Niels, Freitag, Patrick C., Gradinaru, Viviana, Plückthun, Andreas
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.05.2021
• Subjects: Antibodies; Biological Sciences; Drug delivery; Gene therapy; Image resolution; Localization; Paracrine signalling; Pore formation; Surface markers; Toxicity; Tumors; cancer therapy; gene therapy; 3D reconstruction; PACT tissue clearing; adenovirus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2017925118

The goal of cancer-drug delivery is to achieve high levels of therapeutics within tumors with minimal systemic exposure that could cause toxicity. Producing biologics directly in situ where they diffuse and act locally is an attractive alternative to direct administration of recombinant therapeutics, as secretion by the tumor itself provides high local concentrations that act in a paracrine fashion continuously over an extended duration (paracrine delivery). We have engineered a SHielded, REtargeted ADenovirus (SHREAD) gene therapy platform that targets specific cells based on chosen surface markers and converts them into biofactories secreting therapeutics. In a proof of concept, a clinically approved antibody is delivered to orthotopic tumors in a model system in which precise biodistribution can be determined using tissue clearing with passive CLARITY technique (PACT) with high-resolution three-dimensional imaging and feature quantification within the tumors made transparent. We demonstrate high levels of tumor cell–specific transduction and significant and durable antibody production. PACT gives a localized quantification of the secreted therapeutic and allows us to directly observe enhanced pore formation in the tumor and destruction of the intact vasculature. In situ production of the antibody led to an 1,800-fold enhanced tumor-to-serum antibody concentration ratio compared to direct administration. Our detailed biochemical and microscopic analyses thus show that paracrine delivery with SHREAD could enable the use of highly potent therapeutic combinations, including those with systemic toxicity, to reach adequate therapeutic windows.