ABSTRACT
Oncolytic poxviruses have demonstrated initial promising results in patients with cancer in clinical trials, yet further improvements are needed. It has been shown that a single point mutation in the A34R gene resulted in the production of more total progeny virus and more extracellular enveloped virus (EEV), a form that can be immune-evasive and with enhanced spread. We have genetically engineered a new oncolytic poxvirus (designated vA34R) by incorporating this mutated A34R gene into a viral backbone (vvDD) which was designed for tumor-selective replication. This rationally designed virus can evade neutralization from antipoxvirus antibodies and is highly cytotoxic to cancer cells. It demonstrates improved spread and increased replication within the peritoneal cavity resulting in improved antitumor effects in a peritoneal carcinomatosis (PC) model of MC38 colon cancer. Impressively, after carrier cell-mediated delivery in the preimmunized host, vA34R displayed high replication in tumor nodules yet low accumulation in normal tissues thus enhancing the therapeutic index leading to 70% long-term cures. These results demonstrate that vA34R gains an enhanced therapeutic index for PC via immune evasion, increased spread, and production of more progeny virus. Thus, vA34R may be a potent oncolytic virus (OV) for patients with PC, even after prior exposure to vaccinia virus (VV).
Subject(s)
Genetic Vectors/physiology , Mutation , Oncolytic Viruses/physiology , Poxviridae/physiology , Viral Proteins/genetics , Animals , Carcinoma/immunology , Carcinoma/mortality , Carcinoma/therapy , Cell Line, Tumor , Cytopathogenic Effect, Viral , Disease Models, Animal , Female , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Humans , Mice , Oncolytic Virotherapy , Peritoneal Neoplasms/immunology , Peritoneal Neoplasms/mortality , Peritoneal Neoplasms/therapy , Poxviridae Infections/immunology , Poxviridae Infections/virology , Vaccinia virus/physiology , Virus ReplicationABSTRACT
To investigate maturational plasticity of fluid cognition systems, functional brain imaging was undertaken in healthy 8-19 year old participants while completing visuospatial relational reasoning problems similar to Raven's matrices and current elementary grade math textbooks. Analyses revealed that visuospatial relational reasoning across this developmental age range recruited activations in the superior parietal cortices most prominently, the dorsolateral prefrontal, occipital-temporal, and premotor/supplementary cortices, the basal ganglia, and insula. There were comparable activity volumes in left and right hemispheres for nearly all of these regions. Regression analyses indicated increasing activity predominantly in the superior parietal lobes with developmental age. In contrast, multiple anterior neural systems showed significantly less activity with age, including dorsolateral and ventrolateral prefrontal, paracentral, and insula cortices bilaterally, basal ganglia, and particularly large clusters in the midline anterior cingulate/medial frontal cortex, left middle cingulate/supplementary motor cortex, left insula-putamen, and left caudate. Findings suggest that neuromaturational changes associated with visuospatial relational reasoning shift from a more widespread fronto-cingulate-striatal pattern in childhood to predominant parieto-frontal activation pattern in late adolescence.
