Combined immunotherapy with controlled Interleukin-12 gene therapy and immune checkpoint blockade in recurrent glioblastoma: an open-label, multi-institutional phase 1 trial.

Background Veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy in recurrent glioblastoma (rGBM) was reported to show tumor infiltration of CD8 + T cells, encouraging survival, but also up-regulation of immune checkpoint signaling, providing the rationale for a combination trial with immune checkpoint inhibition. Methods An open-label, multi-institutional, dose-escalation phase 1 trial in rGBM subjects (NCT03636477) accrued 21 subjects in 3 dose-escalating cohorts: 1- neo-adjuvant then ongoing nivolumab (1mg/kg) and VDX (10 mg) (n= 3); 2- neo-adjuvant then ongoing nivolumab (3 mg/kg) and VDX (10 mg) (n=3); and 3- neo-adjuvant then ongoing nivolumab (3 mg/kg) and VDX (20 mg) (n=15). Nivolumab was administered 7 (+/- 3) days before resection of the rGBM followed by peritumoral injection of IL-12 gene therapy. VDX was administered 3 hours before and then for 14 days after surgery. Nivolumab was administered every two weeks after surgery. Results Toxicities of the combination were comparable to IL-12 gene monotherapy and were predictable, dose-related and reversible upon withholding doses of VDX and/or nivolumab. VDX plasma pharmacokinetics demonstrate a dose-response relationship with effective brain tumor tissue VDX penetration and production of IL-12. IL-12 levels in serum peaked in all subjects at about Day 3 after surgery. Tumor IFNγ increased in post treatment biopsies. Median overall survival (mOS) for VDX 10 mg with nivolumab was 16.9 months and for all subjects was 9.8 months. Conclusion The safety of this combination immunotherapy was established and has led to an ongoing phase 2 clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).