Bioengineering Advanced Artificial Antigen Presenting Cells for Immunotherapy

Abstract

Abstract Promising cytotoxic (CD8 +) T cell-based cancer therapies have invigorated recent efforts to develop highly tunable, robust, and cost-effective artificial antigen presenting cells (aAPCs) for T cell stimulation both ex vivoand in vivo. Natural APCs, such as dendritic cells (DCs), can be licensed to deliver optimal activation signals (peptide-MHC as S1, costimulatory S2, and cytokine S3) to CD8 +T cells with CD4 +T cell help. While numerous studies demonstrate that “un-helped” CD8 +T cells mount defective responses, many existing therapies overlook this and handicap the function/persistence of the resulting cells. The objective of this study is to synthesize a tri-signal aAPC that couples the CD4 +T cell/DC interaction to stimulate anti-tumor CD8 +T cells. Using novel blends of poly(lactic-co-glycolic acid) (PLGA) and cationic poly(beta-amino-ester) (PBAE) polymers, we synthesized double emulsion microscale aAPCs containing S3 (murine IL-2) encapsulated into the particle core, with S1 (anti-CD3) and S2 (anti-CD28) conjugated to the particle surface. Dynamic Light Scattering measurements show particles of approximately 2 μm in diameter and conjugation efficiency assays showed similar amounts of bound S1 (0.858 μg protein/mg particles) and S2 (0.939 μg protein/mg particles). CD8 +T cell stimulation shows 20-fold proliferation when aAPCs are incubated with CD8 +T cells. Thus, biodegradable PLGA/PBAE aAPCs can recapitulate natural immune cell interactions for optimal CD8 +T cell anti-cancer efficacy. Currently, we are characterizing additional aAPC physicochemical and biological properties. Our novel biomimetic aAPC has both translational relevance and may also shed light on basic T cell biology.