Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
Educating our immune system via vaccination is an attractive approach to combat cancer. Tumor-specific cytotoxic T cells (CTLs) such as CD8+ effector T cells play a critical role in tumor control. However, vaccination aimed at eliciting a potent CD8+ T cell response with tumor-associated peptide antigens, are typically ineffective due to poor immunogenicity. Nanoparticle delivery of antigens and adjuvants can enhance their uptake by antigen presenting cells (APCs) and facilitate their intracellular delivery to induce antigen specific CD8+ cells. PRINT® (Particle Replication in Non-Wetting Template) is a unique platform to fabricate nano and microparticles with exquisite control over size, shape, and surface chemistry. The goal of this study is to design a PRINT® nanoparticle based subunit vaccine for the intracellular delivery of antigenic peptides and adjuvants to induce potent CTLs response. The aims of project include, i) formulation design of nanoparticle subunit vaccine, and induction of ii) in vitro and in vivo immune response. Under the first aim of this study we have engineered a reduction sensitive PRINT® hydrogel based subunit vaccine for intracellular delivery of antigenic peptide SIINFEKL (ovalbumin-derived CTL epitope [OVA257-264 –SIINFEKL]) and an immunostimulatory adjuvant, CpG ODNs (TLR9 agonist). SIINFEKL and CpG ODN were conjugated to PRINT® hydrogel via disulfide linkages. These NPs were successfully internalized and processed by BMDCs, resulting in BMDC maturation, subsequent cross-presentation of antigenic peptide, and induction of potent antigen-specific T cells in mice. Under the second aim of this study we further demonstrated induction of SIINFEKL specific IFN-γ producing CD8+ T cells as well as antitumor protective immune response in EG7 tumor mouse model by delivering sustained release formulations of CSIINFEKL and CpG ODN via PRINT® hydrogel NPs. Taken together, this study provides a highly effective approach, i) to induce potent CTLs response by reduction sensitive NP subunit vaccine and, ii) to induce antitumor immunity by tuning the release of antigenic peptide by changing the conjugation chemistry.