2013 Immunomodulating Anti-Tumor Effects With Telomerase-Mediated Telomere Targeted Therapy and Radiotherapy in Glioblastoma

INTRODUCTION: Human cancers, including GBMs, rely on mechanisms of telomere maintenance to prevent progressive telomere attrition over successive cell divisions, thus enabling replicative immortality. However, GBMs are unique in that ∼90% of cases harbor genetic alterations that promote expression of the Telomerase Reverse Transcriptase (TERT) gene with increased telomerase activity, making telomerase a nearly universal target in GBMs. METHODS: Treat a spontaneous mouse glioma model recapitulating human GBM with an intracranially implanted, immunotherapy-resistant mouse glioma line (SB28; currently the state-of-the-art model for GBMs) with 6-thio-dG, alone or with RT and measure overall survival, toxicity, response biomarkers, and immunophenotype by flow cytometry and spatial transcriptomics. RESULTS: We were able to show that systemic administration of 6-thio-dG (3 mg/kg) led to DNA damage, as indicated by G-H2AX foci. We further found that this damage preferentially appeared near the glioma and not in surrounding tissues and that treating QPP mice with 6-thio-dG led to extended overall survival. Similar results were seen in SB28 bearing mice with utilzation of RT. We found induction of MHC-I by 6-thio-dG and RT and additive (if not synergistic) effects on increasing CD8 cells in the TME. CONCLUSIONS: Collectively, findings from this work has aided will improve our understanding of 6-thio-dG, alone or in combination with RT, in clinically relevant models of GBM; and provide evidence of the mechanism of tumor clearance to aid in the translation of this therapy to clinical trials.