Andreas Plueckthun, PhD, Technology Impact Award Recipient University of Zurich Area of Research: All Cancers Dr. Plueckthun’s team has engineered a SHielded, REtargeted ADenovirus (SHREAD) gene therapy platform that transduces either tumor or stromal cells, based on the chosen surface markers. It delivers the genes encoding secreted therapeutic payload combinations, which then diffuse locally. Upon in vivo administration of these engineered viruses, a subpopulation of cells within the tumor are thus infected, transforming them into therapeutic ‘biofactories’ for the production of secreted therapeutics which act on neighboring cells in a paracrine fashion (termed ‘paracrine delivery’).Recently, they showed that tumor and tumor stromal cells such as fibroblasts can be used to produce full-length anti-cancer monoclonal antibodies identical in composition to those produced commercially, even exhibiting similar glycosylation patterns and thus effector functions. Additionally, they’ve shown that paracrine delivery is massively advantageous in localizing high concentrations of therapeutic antibodies to the tumor where their actions are needed, with only very low amounts diffusing into systemic circulation where they could cause off-target effects.Overall, there was an 1800-fold improvement in tumor-to-serum concentration gradient in comparison to direct administration of the same recombinant antibody. This localizing effect could have a transformative effect on the field of cancer immunotherapy, as in situ production could add a layer of specificity to immunomodulation, significantly reducing systemic immune-related adverse effects. Furthermore, this approach could enable the use of very aggressive immunotherapeutics for safe indications in cancer immunotherapy. Here, Dr. Plueckthun is developing the SHREAD platform for the delivery of immunomodulators often deemed ‘too toxic’ for systemic therapies, including costimulatory agonists, proinflammatory cytokines, BiTEs, SAg, and more. Projects and Grants The SHREAD gene therapy platform for the safer delivery of Narrow Therapeutic Index (NTI) immunotherapeutics directly to the tumor microenvironment University of Zurich | All Cancers | 2021
