The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)
INTRANASAL HPV PEPTIDE VACCINE FORMULATION INDUCES POTENT CYTOTOXIC CD8 T CELL IMMUNITY FOR THE TREATMENT OF GENITAL HPV TUMORS
Author ORCID Identifier
Date of Graduation
Doctor of Philosophy (PhD)
Jagannadha Sastry, Ph.D.
Joya Chandra, Ph.D.
Shao-Cong Sun, Ph.D.
Greg Lizee, Ph.D.
Pamela Wenzel, Ph.D.
Human Papillomavirus (HPV) induced cancers continue to affect millions of women worldwide, with the five year survival rate hovering just under 60% in some demographics. Therefore there is an unmet need to develop effective, yet, easily administered therapies to treat established HPV genital lesions. Even though immune checkpoint therapy (ICT) is a promising treatment option in some HPV+ cancers, the high cost and associated toxicities are still major concerns for their widespread application. HPV cancers are textbook candidates for therapeutic vaccination intervention because they’re driven by the expression of viral oncoproteins E6 and E7, which serve as ideal tumor specific antigen targets. An effective therapeutic vaccine should be able to overcome tumor mechanisms of immune-evasion and immune-suppression, while inducing a robust anti-tumor mediated response. In this dissertation I investigated a novel therapeutic HPV peptide vaccination strategy; by incorporating two diverse acting adjuvants for induction of strong cytotoxic effector immunity, and utilizing the intranasal mucosal route of immunization to ensure efficient trafficking to the genital mucosal tumors. Overall, I hypothesized that intranasal HPV peptide vaccination employing the combination of TLR9 and NKT cell ligands, (CpG-ODN and α-GalCer, respectively) will induce potent systemic and mucosal antigen-specific CD8 T cell response, specifically at the female reproductive tract (FRT) to eliminate HPV genital tumors.
Utilizing an orthotopic vaginal tumor model in mice, I obtained evidence demonstrating the efficacy of the therapeutic HPV peptide vaccine containing α-GalCer and CpG-ODN (TVAC), in terms of inducing sustained and efficient tumor regression in nearly 85% of treated mice. The therapeutic efficacy correlated with significant CD8 T cell responses and increased ratios of cytotoxic effector to immune suppressive populations (regulatory T cells and myeloid derived suppressor cells) in the tumor microenvironment. Treatment with TVAC was also effective against tumors implanted in the flank, representing a systemic HPV tumor model. These results support the feasibility and benefits of utilizing intranasally delivered therapeutic vaccines formulated with combinations of diverse acting adjuvants, such as the TVAC tested in this investigation, as a potential strategy for clinical development to treat established genital HPV tumors.
Therapeutic Vaccine, HPV, Immunology, alpha-Galactosylceramide, CpG-ODN, Intranasal vaccine, genital tumors