Genetically Stable Poliovirus Vectors Activate Dendritic Cells and Prime Antitumor CD8 T Cell Immunity
General Material Designation
[Thesis]
First Statement of Responsibility
Mosaheb, Mohammad Mubeen
Subsequent Statement of Responsibility
Gromeier, Matthias
.PUBLICATION, DISTRIBUTION, ETC
Name of Publisher, Distributor, etc.
Duke University
Date of Publication, Distribution, etc.
2019
PHYSICAL DESCRIPTION
Specific Material Designation and Extent of Item
136
DISSERTATION (THESIS) NOTE
Dissertation or thesis details and type of degree
Ph.D.
Body granting the degree
Duke University
Text preceding or following the note
2019
SUMMARY OR ABSTRACT
Text of Note
Viruses naturally engage innate immunity, induce antigen presentation, and mediate CD8 T cell priming against foreign antigens. Polioviruses can provide a context optimal for generating antigen-specific CD8 T cells, as they have natural tropism for dendritic cells, preeminent inducers of CD8 T cell immunity; elicit Th1-promoting inflammation; and lack interference with innate or adaptive immunity. However, notorious genetic instability and underlying neuropathogenicity has hampered poliovirus-based vector applications. We devised a strategy based on the polio:rhinovirus chimera PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in human subjects, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate, and induce epitope presentation in DCs in vitro; recruit and activate DCs with Th1-dominant cytokine profiles at the injection site in vivo. They efficiently prime tumor antigen-specific CD8 T cells in vivo, induce CD8 T cell migration to the tumor site, delay tumor growth and enhance survival in murine tumor models.