Formulation and Delivery
Jayanth Panyam, PhD (he/him/his)
Dean and Professor
University of Washington
Seattle, Washington
Anette Mullertz, PhD, FAAPS
Professor
University of Copenhagen
Copenhagen OE, Hovedstaden, Denmark
Agonists of toll like receptors (TLRs) are promising anticancer vaccine adjuvants because of their ability to induce proinflammatory cytokines necessary to generate a robust immune response. However, currently available TLR agonists suffer from a number of limitations including self-regulatory immunosuppression and unfavorable local pharmacokinetics resulting in poor availability within dendritic cells. Further, current TLR agonist-based anticancer vaccines generate a robust cytotoxic CD8 T cell response but not CD4 Th1 helper T cell response, which is critical for induction of effective, long-term antitumor immunity. We are addressing these important challenges through a synergistic combination of drug discovery and drug delivery efforts. Our team has developed a suite of highly substituted imidazoquinolines, which activate TLR 7 and/or 8 and induce significantly higher levels of cytokines compared to imiquimod, an FDA approved TLR7 agonist. Our studies show the balance between pro-inflammatory and immunosuppressive cytokines can be tuned through structural modifications. Encapsulation of these agonists in acidic pH responsive nanoparticles result in robust activation of CD4 and CD8 T cells as well as natural killer cells, leading to a stronger anticancer immune response than free agonist. In a separate line of investigation, intradermal delivery of nanoparticle vaccine using a hollow microneedle platform led to an enhanced Th1 immune response, which is essential for effective induction of long-term anti-tumor immunity. By identifying new design principles and delivery strategies for TLR agonists, we expect our studies will further advance the field of cancer immunotherapy.