(505f) Computationally-Designed Nanomaterials for Cancer Immunotherapy

The stability of lipid nanoparticles at drug concentrations required for clinical efficacy has been a major challenge in the clinical translation of these nanomedicines. To overcome these challenges, we have developed a platform technology, called supramolecular therapeutics, where we design small molecular subunits that act as active drugs but like LEGO blocks can self-assemble with each other and with additional inactive excipients through weak, non-covalent interactions to form nanoscale structures. To engineer the supramolecular therapeutics, we have designed an in silico platform technology, which allow us to design the building blocks that can undergo stable supramolecular structures. We achieve this by integrating a quantum mechanical optimization of minimum energy states with an all atomistic simulation of the optimized structures interacting with each other and the excipients. The supramolecular therapeutics exhibit unique ability to home into the tumor. We used this platform technology to inhibit oncogenic drivers in the tumor as well as kinase signaling pathways in immune suppressive cells in the tumor microenvironment. We observed that supramolecular therapeutics result in a sustained inhibition of the target and the downstream signals, thus offering a spatial (preferentially within the tumor) and temporal control over signal transduction pathways that are implicated in tumorigenesis. This study shows that a successful strategy to overcome immune suppression and improve cancer immunotherapy could be devised by using computationally-designed supramolecular nanotherapeutics that can alter the innate immune contexture of tumors by switching the immunosuppressive cells to effector cells. This study therefore can have a significant impact not only in advancing fundamental knowledge on the focal manipulation of innate immunity in the tumor, but also advance a novel immunotherapy that can potentially dramatically increase survival.