Abstract IA07: Genetic engineering of therapeutic T cells using synthetic nanoparticles

Abstract Despite the obvious advantages afforded by targeted T-cell cancer therapies (compared with the blunt instruments of chemotherapy, radiotherapy, and surgery), the complexity and costs involved in producing genetically modified lymphocytes remain major obstacles to their implementation as standard of care. Work in our laboratory aims to obviate these problems by integrating materials science, immunology, and gene therapy to make cellular immunotherapy more effective, practical, and widespread. In this talk, I will highlight two examples: In the first segment, I will describe a new strategy to genetically imprint therapeutically desirable phenotypes in cultured T cells, simply by mixing them with a targeted mRNA-carrying nanoreagent. When they are added to a culture of cells, these engineered nanoparticles bind to targeted T cell populations and induce major biologic effects on the basis of transient “hit-and-run” gene therapy without the necessity of resorting to complicated protocols or complex ancillary equipment. Our approach provides significant advantages over those currently used to create cytoreagents (i.e., viral transfection and electroporation), which require specialized equipment and demanding production steps. In the second part of my presentation, I will introduce a new injectable reagent our group developed that that can quickly program tumor-recognizing capabilities into circulating T cells without the need for laboratory manipulations. We demonstrate that, once they are adapted with lymphocyte-targeting ligands, polymeric nanocarriers can selectively deliver leukemia-specific chimeric antigen receptor (CAR) genes into host T cells in situ. These nanoparticles are easy to manufacture and are stable, which simplifies long-term storage and reduces cost. This technology may therefore provide a practical, broadly applicable treatment that can generate antitumor immunity at the time of diagnosis in a variety of settings. Citation Format: Howell F. Moffett, Tyrel T. Smith, Matthias T. Stephan. Genetic engineering of therapeutic T cells using synthetic nanoparticles [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA07.