Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity

Abstract

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. Here 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; they 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.

Viral infection of cells within the tumor microenvironment mediates antitumor immunotherapy via selective TBK1-IRF3 signaling

“…5a ). PVSRIPO translation (viral 2C expression) peaked early (8 hpi) and faded thereafter, consistent with prior observations of viral translation restrained by host innate defenses in infected myeloid cells 7 , 8 . P-IRF3(S396)–a marker of IRF3 activation—was potently induced in PVSRIPO-infected MDMs, but less responsive to LPS (Fig.…”

“…For virus co-implantation experiments using E0771, tumor cells were co-implanted with the addition of mock (DMEM) or mRIPO (1 × 10 7 pfu). For the generation of BMDCs, isolated bone marrow cells from femurs and tibias were cultured at a density of 2.5 × 10 6 cells/ml in RPMI + 10% FBS containing 300 ng/ml human recombinant FLT3L (Thermo-Fisher) for 9 days and non-adherent cells were used 8 . FLT3L-derived BMDCs were tested for CD11c expression by flow cytometry (CD11c-APC at 1:100, Biolegend).…”

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy

“…Possibly suggesting an immune subversive mechanism: low TMB also associated with higher MDSC/myeloid cell density within tumors ( Supplementary Fig. 4c, d), cell types well-known for suppressing effector functions of antitumor T cells 20 -including via the PD1/PD-L1 axis [21][22][23] -that are also potentially reprogrammed by PVSRIPO therapy 3,24 . Alternatively, as a shorter time to recurrence also correlates with lower TMB and favorable response to PVSRIPO, shorter duration of SOC, or shorter time from initial surgery, may allow for superior response to immunotherapy.…”

Human Vaccines & Immunotherapeutics: news

“…Enhanced survival in a mouse model of diffuse midline glioma and elimination of cancer cells in vitro was induced by a histone-based epitope carried by a chimeric poliorhinovirus vector. 6 The principle had been shown before in glioblastoma patients. Diffuse midline glioma is an extremely HUMAN VACCINES & IMMUNOTHERAPEUTICS 2020, VOL.…”