Poly-Nucleic acid complexes for chemokine modulation of the tumor microenvironment

Duke University, Durham NC

Investigators

Abstract

Nucleic acids are poised to become the next generation of cancer therapeutics, and the current standard for nucleic acid delivery is lipid nanoparticles. Lipid nanoparticles can effectively deliver mRNA and siRNA in vaccine and therapeutic settings, both preclinically and clinically. This work seeks to develop a polymer-based delivery system for nucleic acids, which may hold multiple advantages over current lipid nanoparticle technologies. A Poly(2-0xazoline) platform for delivering mRNA can produce smaller particles sizes and utilize PEG alternatives in forming polymer-nucleic acid complexes. Smaller sized particles can reduce the significant passive accumulation in the liver and non-PEG polymers can mitigate anti-PEG antibody-based responses. This proposal will investigate these particles in the setting of triple negative breast cancer. Triple negative breast cancer is heterogeneous and highly immunosuppressive, with poor infiltration of key immune cells rendering modern therapies ineffective. By increasing the presence of these key immune cells, therapeutic outcomes can be improved in triple negative breast cancer. This work proposes to deliver mRNA for the key chemokine, CXCL 1, to recruit conventional type 1 dendritic cells to the tumor. These cells are responsible for identifying tumor antigens, translocating to the lymph node, and training T-cells to identify and combat cancer cells. With increased T-cell infiltration, tumors will increase in their sensitivity to checkpoint inhibitor therapy, a critical piece of current treatment paradigms. Our polymer-nucleic acid complexes will target cancer associated fibroblasts, the most abundant cell in the tumor microenvironment, for CXCL 1 mRNA delivery. Aptamers targeting cancer associated fibroblasts will allow us to improve mRNA delivery efficiency to the solid tumor, while mitigating potential side effects from off-target delivery. By hijacking cancer associated fibroblasts, we can utilize a cell which is a key regulator of the immunosuppressive microenvironment to attract dendritic cells to the tumor for antigen presentation-making them a key contributor to the anti-cancer response. Dendritic cells will go on to present antigen to T-cells, priming them for anti-cancer activity and homing to the tumor. This will sensitize these tumors to checkpoint inhibitor therapy by increasing the number of T-cells in the tumor. The successful completion of this project will validate the use of targeted polymer-nucleic acid complexes for gene delivery and demonstrate the viability of chemokine-based treatment paradigms. This is the first step towards chemokine-cocktail immunotherapies, which could target multiple immune cell populations for precision activation of the immune system against cancer.