Abstract 6511: Immunocompetent large animal model of mesenchymal glioblastoma achieved through somatic gene editing technology

Glioblastoma multiforme (GBM) is the most common primary brain tumor. GBM tumors are invasive and highly proliferative, with less than 3% of patients surviving five years from initial diagnosis. Current standard of care treatment consists of surgical resection, radiation, and chemotherapy, and despite this aggressive treatment, nearly all patients succumb to disease recurrence. GBM tumors have heterogeneity, high mutation rates, infiltrating growth, and a complicated tumor-immune microenvironment making treatments difficult and complex. Additionally, therapies must cross the blood brain barrier, a significant problem preventing therapeutic efficacy. Novel drugs, promising therapeutic targets, and new targeting strategies frequently fail in late Phase 2 and Phase 3 clinical trials due to lack of efficacy. The therapies often show effectiveness in a subset of patients, but fail in the majority, leading to clinical trial failure. Because GBM clinical trials are not enrolled based on patient specific biomarkers or genetic subtypes, precision medicine approaches have faced an uphill battle for a patient population that is too small for multiple concurrent clinical trials and a disease with a severe lack of predictive preclinical models. GBM tumors fall into three subtypes, mesenchymal, classical and proneural, each with distinct genetic profiles. Variations in progression and survival and differences in therapeutic response suggest that each subtype should be treated with a regimen unique to that subtype. Roughly 30-50% of GBMs are characterized as mesenchymal, the most common and aggressive subtype. In this study, we demonstrate the development of a large animal (mini pig), immunocompetent model of mesenchymal GBM, using stereotactic delivery of gene editing reagents. 50% of injected animals rapidly develop reproducible tumors that genetically and immunologically resemble human tumors, making this an ideal preclinical model for therapeutic development and biomarker identification. Importantly, tumors can be detected within weeks of injection through a simple, cost-effective blood-based assay. Cell lines developed from these tumors show temozolomide sensitivity and provide an opportunity for high throughput drug screening prior to animal trials. Therillume is utilizing these animals to identify, develop, and validate novel drugs, prognostic and diagnostic biomarkers, therapeutic devices, and effective drug delivery strategies. In particular, Therillume has focused on identifying targeted therapies that previously failed in clinical trials, despite showing efficacy in a subset of patients, and validating the safety and efficacy of these therapies in animals that have a companion biomarker that predicts therapeutic efficacy, in hopes of developing new strategies for clinical trials that will enable biomarker-driven therapeutic development and success. Citation Format: Nicholas Koes, Mandy Taisto, Barbara R. Tschida, Daniel F. Carlson, Maryam Aftabizadeh, H Nayanga Thirimanne, Eric C. Holland, Massimo D'Apuzzo, Christine E. Brown, Adrienne L. Watson. Immunocompetent large animal model of mesenchymal glioblastoma achieved through somatic gene editing technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6511.