Bringing precision medicine to glioblastoma patients by modeling molecular tumor subtypes in immunocompetent swine for therapeutic and biomarker development

Abstract Glioblastoma (GBM) is an aggressive primary brain tumor with no effective cure. Standard of care treatment offers dismal prognoses for patients with a median survival time of only 15.6 months, and no new drugs have been approved in 15 years. Contributing factors include tumor heterogeneity, high mutation rates, infiltrative growth, a complex tumor-immune microenvironment, and the blood-brain barrier, all of which are obstacles clinicians and researchers must overcome to improve patient outcomes. Research to identify novel therapeutic strategies are ongoing, but treatments that show promise in preclinical studies often do not pass Phase 2 and 3 clinical trials. These costly failures are attributable to a lack of predictive preclinical models that translate to human application, low patient availability for numerous and robust clinical trials, and an “all-comer” approach to clinical trial design where patients are enrolled based on disease presence and not molecular features of the tumor. To advance treatments for GBM, Recombinetics has pioneered somatic gene-editing technologies to the same genetic changes seen in patient tumors in GBM-initiating cells in an immune-competent swine model. These models rapidly and reproducibly develop GBM tumors that resemble human GBMs genetically, clinically and histologically. In addition to the physiological, immunological, and metabolic parallels between swine and humans, the molecular data collected from our swine mesenchymal and classical subtypes of GBM validate accurate disease modeling and we are pursuing additional GBM subtypes. Using RNA-sequencing, we are characterizing molecular profiles of these tumors, as well as identifying and validating drug targets. Studies are ongoing to characterize the tumor immune microenvironment of our models for improved immune-oncology therapeutic development. These large animal models of GBM will usher in a new era of pre-clinical testing that predicts the efficacy of a variety of therapeutic approaches, using precision medicine to bring novel, safe, and effective therapies to patients.