DDDR-66. Leveraging protease-resistant IGFBP2 to sensitize glioblastoma to oncolytic HSV therapy

Abstract The prognosis for Glioblastoma (GBM) remains grim despite remarkable advances in gene- and immune-targeted therapies, underscoring the urgent need for novel approaches. Oncolytic herpes simplex virus-1 (oHSV) has shown promise in clinical trials; however, efficacy remains limited to a small subset of patients. Identifying intrinsic (e.g., tumor-heterogeneity) and extrinsic (e.g., local/systemic immunosuppression) resistance mechanisms is therefore paramount. We previously identified a novel mechanism-of-resistance to oHSVs in which viral infection induces tumor cells to secrete Insulin-like growth factor 2 (IGF2) and stromal cells to secrete IGF1. Subsequent autocrine and paracrine activation of Insulin-like Growth Factor-1 Receptor (IGF1R) promotes tumor regrowth and resistance. While IGF1R blockade enhanced oHSV efficacy, clinical application is limited by poor biodistribution and off-target effects. Insulin-like growth factor binding-protein 2 (IGFBP2) binds IGFs with higher affinity than IGF1R, making it a promising peptide inhibitor. Paradoxically, high IGFBP2 levels correlate with poor GBM prognosis, as its IGF-independent functions (i.e., α5β1-integrin binding) broadly support tumor progression. Additionally, MMP9-mediated cleavage reduces IGF-binding affinity while preserving IGF-independent actions. Herein, we found that oHSV treatment induces MMP9 expression and suppresses endogenous IGFBP2 secretion, promoting IGF-dependent and independent resistance. To overcome this, we developed a next-generation oHSV, oHSV-BP2mt, which secretes protease-resistant IGFBP2 with a mutated RGD domain, thereby targeting both IGF-dependent and IGF-independent resistance. Interestingly, while oHSV-BP2mt enhanced efficacy across all tested GBM cells, its anti-tumor effect was more pronounced in oHSV-resistant cells (low IGFBP2), accompanied by enhanced replication and spread. oHSV-BP2mt dramatically improved survival in orthotopic models of oHSV-sensitive (high IGFBP2) GBM, with 60% of mice surviving over 100 days, compared to 10% with control oHSV. Notably, a single injection of oHSV-BP2mt is comparable to daily pharmacologic IGF1R blockade for one month. Collectively, these findings provide compelling preclinical evidence for the therapeutic promise of oHSV-BP2mt in advancing care for patients with GBM.