Particulate Delivery of Innate Immune Agonist for Cancer Immunotherapy

Abstract

Abstract Immunotherapies have dramatically improved cancer patient survival; however, certain forms of cancer still rely on conventional chemotherapies and radiation. We have designed a novel cancer treatment that utilizes an immunotherapeutic to augment the adaptive immune system. Many FDA-approved immunotherapies have several drawbacks including high cost, short half-life, and flu-like side effects leading to patient noncompliance. To overcome these difficulties, we have utilized pathogen-associated molecular patterns (PAMP) to stimulate an innate immune response and induce a potent cytokine response. However, the receptor for the PAMP is located in the cytosol, and the PAMP cannot transverse the cell membrane. To overcome this, we have designed a polymeric microparticle (MP) to deliver the PAMP (PAMP MPs) into the cytosol. The polymeric MP is composed of a dextran-based, biodegradable polymer. It has several critical advantages over other FDA-approved delivery vehicles, such as liposomes, including greater stability, higher encapsulation efficiency (EE) of hydrophilic cargo, ease and reproducibility of production, and ease of end point sterilization. Treatment with PAMP MPs resulted in reduced tumor burden compared to mice treated with the soluble PAMP in a model of melanoma, suggesting that the MPs increase the biological activity. Intratumoral treatment with PAMP MPs resulted in increased natural killer cells and professional antigen presenting cells in the tumor environment. In conclusion, our PAMP MPs resulted in significant anti-tumor efficacy in an aggressive murine model of melanoma, and the data suggest that this anti-tumor function is due to an increased immune response within the tumor.