ATIM-25. PD-1 INHIBITION CAN BE COMBINED WITH IL-12 IN SUBJECTS WITH RECURRENT GLIOBLASTOMA

Abstract Monotherapy with intratumoral Ad-RTS-hIL-12 (Ad), a novel gene therapeutic conditionally expressing IL-12 under the transcriptional control of oral veledimex (V, 20 mg) acting via the proprietary RheoSwitch Therapeutic System® (RTS®), was shown in a phase 1 Main study (NCT02026271) to elicit a sustained intra-tumoral activated cytotoxic T-cell response with co-expression of PD-1. Additionally, the Main study showed improved median overall survival (mOS), compared to historical controls, in subjects with recurrent glioblastoma (rGBM) receiving Ad + V. Herein, we report updated findings from on an ongoing open label, dose-escalation Phase 1 substudy (NCT03636477) evaluating safety and tolerability of local, controlled IL-12 plus nivolumab in adult subjects with rGBM. Ad was administered by single intratumoral injection (2 x 1011 viral particles) on Day 0 plus V (10 and 20 mg) PO QD x 15 with nivolumab (1 and 3mg/kg) IV on Days -7, 15, then Q2W. Subjects have been accrued into three cohorts and follow-up is ongoing. Data from all three cohorts regarding dose escalation of V and nivolumab will be presented. The initial safety profile during V dosing period was similar to Ad+V monotherapy with adverse reactions being dose-related and rapidly reversible upon discontinuation of V. And those adverse reactions during the follow on nivolumab dosing were tolerable and manageable and consistent with nivolumab labeling, with no synergistic toxicities, and drug-related deaths. In the first two cohorts (where data is available), combination therapy improved the biomarker “cytoindex” (ratio of circulating CD8+ T cells to FoxP3+ regulatory T cells). (In the Main study, cytoindex correlated with overall survival). Controlled IL-12 production using Ad+V with nivolumab is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile. Further phase 2 investigation of Ad+V plus a checkpoint inhibitor in rGBM is planned.