title: Investigation of phosphorylated adjuvants co-encapsulated with a model cancer peptide antigen for the treatment of colorectal cancer and liver metastasis.
abstract: The lipid calcium phosphate nanoparticle is a versatile platform capable of encapsulating a wide range of phosphorylated molecules from single nucleotides to pDNA. The use of this platform has shown great success as an immunotherapeutic vaccine carrier, capable of delivering co-encapsulated phosphorylated adjuvants and peptides. Three potent vaccine formulations were investigated for anti-cancer efficacy. The phosphorylated adjuvants, CpG, 2'3'cGAMP, and 5'pppdsRNA were co-encapsulated with a model phosphorylated tumor specific peptide antigen (p-AH1-A5). The anti-cancer efficacy of these adjuvants was assessed using an orthotopic colorectal liver metastasis model based on highly aggressive and metastatic CT-26 FL3 cells implanted into the cecum wall. The results clearly indicate that the RIG-1 ligand, 5'pppdsRNA, co-encapsulated with the p-AH1-A5 peptide antigen greatly reduced the growth rate of the primary colon cancer as well as arrested the establishment of liver metastasis in comparison to the other adjuvant formulations and unvaccinated controls. Further evaluation of the immune cell populations within the primary tumor confirms the ability of the 5'pppdsRNA adjuvant to boost the adaptive CD8+ T-cell population, while not inciting increased populations of immune suppressive cell types such as T-regulatory cells or myeloid derived suppressor cells. Furthermore, to our knowledge this is the first study to investigate the anti-cancer efficacy of a specific RIG-1 receptor ligand, 5'pppdsRNA, alongside more established TLR 9 (CpG) and STING (2'3'cGAMP) adjuvants in a cancer vaccine. The 5'pppdsRNA vaccine formulation can be a potent immunotherapy, especially when combined with agents that remodel the immune suppressive microenvironment of the tumor.
authors.affiliation: Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Goodwin
authors.affiliation: Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: leafh@email.unc.edu.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage* / Q000009:adverse effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000150:complications* / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary* / Q000628:therapy*; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000628:therapy; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D010455:Peptides
keywords: 2′3′cGAMP; 5′pppdsRNA; AH1; Colorectal cancer; Colorectal liver metastasis; CpG; Lipid calcium phosphate nanoparticles; Phosphorylated adjuvants; Phosphorylated peptide antigen; Vaccine; p-AH1-A5