CReP mediates selective translations initiation at the endoplasmic reticulum
Science Advances (June 2020)
This study reports on the role of the constitutive repressor of elF2a phosphorylation (CReP) in translation of poliovirus and the endoplasmic reticulum (ER). Research revealed that CReP, through binding elF2a, anchors translation initiation machinery at the ER and enables local protein synthesis in this compartment. This ER site was protected from the suppression of cytoplasmic protein synthesis by acute stress responses, e.g., phosphorylation of elF2a(S51). This study proposes that partitioning of translation initiation machinery at the ER enables cells to maintain active translation during stress conditions associated with global protein synthesis suppression.
Genetically stable poliovirus vectors activate dendritic cells and prime antitumor CD8 T cell immunity
Nature Communications (January 2020)
Poliovirus is 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 interreference with innate or adaptive immunity. This study devised a strategy based on PVSRIPO, devoid of viral neuropathogenicity after intracerebral inoculation in humans, for stable expression of exogenous antigens. PVSRIPO vectors infect, activate and induce epitope presentation in dendritic cells. They recruit and activate dendritic cells at the injection site, prime tumor antigen specific CD8 T cells, migrate CD8 T cells to the tumor site, delay tumor growth and enhance survival.
Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs
Science Translational Medicine (September 2017)
Tumors thrive in an immunosuppressive microenvironment that impedes antitumor innate and adaptive immune responses. Approaches that can overcome immunosuppression and engage antitumor immunity are needed. This study defines the adjuvant and cancer immunotherapy potential of the recombinant poliovirus/rhinovirus chimera (PVSRIPO). PVSRIPO’s immune adjuvancy stimulates canonical innate anti-pathogen inflammatory responses within the tumor microenvironment that culminate in dendritic cell and T cell infiltration. Our findings provide mechanistic evidence that PVSRIPO functions as a potent intratumor immune adjuvant that generates tumor antigen–specific cytotoxic T lymphocyte responses.
A Phase I Trial of Intratumoral PVSRIPO in Patients with Unresectable Treatment Refractory Melanoma
The Society for Immunotherapy of Cancer (SITC) 35th Anniversary Annual Meeting (2020)
Results from Phase I clinical data presented at SITC’s annual meeting found that PVSRIPO activates innate and adaptive immunity to facilitate a targeted anti-tumor immune response in patients with unresectable melanoma. Among the six patients who received three PVSRIPO injections without any other concomitant therapy, the overall response rate was 67%, suggesting that PVSRIPO was able to initiate or rekindle responses in patients who have failed anti-PD-1 therapy. Response in both injected and un-injected tumors (e.g. abscopal response) were observed.