IMPS-03: INTRATUMORAL REGULATED EXPRESSION OF IL-12 AS A GENE THERAPY APPROACH TO TREATMENT OF GLIOMA

Immunotherapy is an attractive approach for glioma therapy. We have developed a replication-incompetent adenovirus engineered to express IL-12 (Ad-RTS-IL-12), via our RheoSwitch Therapeutic System^® (RTS^®) gene switch, injected directly into a tumor. IL-12 expression is "off" devoid of the activator ligand, veledimex, while IL-12 production is turned "on" (in a dose-dependent manner) by oral administration of veledimex. Mechanistic studies in numerous syngeneic mouse tumor models with Ad-RTS-mIL-12 + veledimex have demonstrated a dose-related increase in tumor IL-12 mRNA and IL-12 protein expression. Discontinuation of veledimex resulted in a return to baseline IL-12 mRNA and protein expression. These changes correlated with a local and systemic immune and anti-tumor response. Veledimex crossed the blood-brain-barrier in both naive and orthotopic GL-261 mice with increased brain tissue level of ∼6 fold observed in tumor bearing vs. normal mice (1950 ± 573 and 324 ± 51ng/g). Based on these findings the effects of Ad-RTS-mIL-12(5e9vp) + veledimex were studied in the following cohorts; dexamethasone, bevacizumab, temozolamide and CD279 (PD-1 inhibitor). Ad-RTS-mIL-12 + veledimex demonstrated a dose-related increase in survival without significant adverse events. At Day 92 (study termination), 50% of the animals that received veledimex at 100mg/m²/day for 14 consecutive days were alive and tumor free with peak tumor IL-12 at Day 3 of ∼240pg/mg. In contrast, the mean survival for the other groups were: vehicle 18d, dexamethasone 24d, bevacizumab 25d, temozolamide 40d and CD279 38d demonstrating that this novel regulated immunotherapeutic approach may be an effective form of therapy for glioma. A Phase 1 study of Ad-RTS-hIL-12 + veledimex in patients with recurrent or progressive malignant glioma are stratified into two groups: resection plus localized injection or stereotactic injection (3D-located) of Ad-RTS-hIL-12 (single intratumoral injection) + veledimex 14 days (oral) has initiated. The primary endpoint is the safety and tolerability of Ad-RTS-hIL-12 + veledimex with secondary endpoints of MTD, immune response, objective response rate, disease progression, progression-free and overall survival.