Published Research in Nature Communications: Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity
Journal authors for the below study:
Mubeen M. Mosaheb, Elena Y. Dobrikova, Michael C. Brown, Yuanfan Yang , Jana Cable, Hideho Okada, Smita K. Nair, Darell D. Bigner, David M. Ashley & Matthias Gromeier
Viruses naturally engage innate immunity, induce antigen presentation and mediate CD8 T cells priming against foreign antigens. This study shows that poliovirus can generate antigen-specific CD8 T cells, elicit Th1-promoting inflammation and do not interfere with innate or adaptive immunity. However, there is a lot of genetic instability and neuropathogenicity that has hindered progress in research on poliovirus-based vector applications.
In this study researchers created a methodology based on the polio-rhinovirus chimera (PVSRIPO) which is absent of viral neuropathogenicity in intracerebral inoculation, for a more stable expression of exogenous antigens. To achieve genetic stability, researchers found that inserts must be functionally integrated into the genome in order to contribute to viral fitness. After injected, PVSRIPO vectors are able to efficiently prime antigen-specific CD8 T cells and help them migrate to the tumor site to ultimately delay growth and enhance survival.
Methods like these, called cancer vaccines, failed in earlier trials due to lacking engagement from dendritic cells (DCs). Essentially, peptide vaccination without proper DC costimulation and proinflammatory cytokines can induce tolerance or T cell anergy. In the study, researchers show that pharmacokinetic problems of cancer vaccinations (e.g. poor uptake/presentation by DCs) are solved with PVSRIPO vectors. PVSRIPO vectors naturally target dendritic cells for infection and it’s DC-stimulating phenotype starkly contrasts with the immune evasion and suppression programs of many human pathogenic viruses.
PVSRIPO vectors elicit tumor antigen-specific cytoxic T lymphocytes capable of infiltrating distant tumors, reducing tumor burden and significantly increasing survival in immunocompetent tumor models. The vector accommodates any insert, provided that the salient design principles of our approach are considered. Thus, researchers outlined a clinically feasible enterovirus vector approach based on PVSRIPO that has a clinical track record of safe administration, has empirical evidence genetic stability, and is capable of unique proinflammatory engagement of DCs for priming of CD8 T cells.
For the full published study click the PDF button to the right.