Our laboratory is exploring the science of immune rejection of tumors, spanning from basic mechanistic research of innate immune sensing to clinical translational cancer immunotherapy.
Our clinical approach is informed by RNA virus:host interactions and their potential for eliciting tumor immune surveillance in cancers that do not respond to any therapy. Our focus is on members of the Enterovirus genus of the Picornavirus family, mainly because of their unique RNA genome structure and innate immune signature. Specifically, we are pursuing immunotherapy with PVSRIPO, the live attenuated poliovirus type 1 (Sabin) vaccine carrying an internal ribosomal entry site (IRES) of human rhinovirus type 2 (HRV2). PVSRIPO is profoundly attenuated, with lacking cytopathogenicity yielding an intriguing innate pattern. It has shown promise in Phase-1 clinical trials in recurrent glioblastoma and in recurrent, non-resectable melanoma:
PVSRIPO. Poliovirus +sense RNA genomes contain internal ribosomal entry sites (IRES) that enable viral protein synthesis by recruiting the translation initiation scaffold eIF4G. The polio (Sabin) vaccines carry attenuating IRES point mutations in the eIF4G footprint. The eIF4G ‘landing pad’ in the HRV2 IRES is poorly conserved. PVSRIPO is engineered for profound attenuation, loss of cytopathogenicity, and an accentuated innate antiviral signaling phenotype. See Gromeier et al. (PNAS, 1996, PMCID: PMC39803).
https://www.pnas.org/doi/abs/10.1073/pnas.93.6.2370
