Veledimex-regulatable interleukin-12 gene therapy combined with immune checkpoint inhibition is safe in recurrent glioblastoma

According to a latest study, use of veledimex (VDX)-regulatable interleukin-12 (IL-12) gene therapy combined with immune checkpoint inhibition is safe in recurrent glioblastoma (rGBM). An update of this phase I trial was published in the journal Neuro-Oncology.

VDX-regulatable IL-12 gene therapy has shown tumor infiltration of CD8+ T cells, encouraging survival, but also up-regulation of immune checkpoint signaling. This open-label, multi-institutional phase I trial was conducted to demonstrate the safety of combined immunotherapy. For the study, 21 rGBM subjects were accrued in 3 dose-escalating cohorts: (1) neoadjuvant then ongoing nivolumab (1mg/kg) and VDX (10 mg) (n = 3); (2) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (10 mg) (n = 3); and (3) neoadjuvant then ongoing nivolumab (3 mg/kg) and VDX (20 mg) (n = 15). 7 (±3) days before resection of the rGBM nivolumab was administered, followed by peritumoral injection of IL-12 gene therapy. VDX was administered 3 hours before and for 14 days after surgery. Nivolumab was administered every two weeks after surgery.

The toxicities of the combination were comparable to IL-12 gene monotherapy and were predictable and dose-related, which could be reversed by stopping the doses of VDX and/or nivolumab. A dose-response relationship was observed 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. The median overall survival (mOS) for VDX was 16.9 months with 10mg of nivolumab and for the rest of the subjects was 9.8 months.

Hence, the result of this study has established the safety of this combination immunotherapy, which has paved the way for ongoing phase II clinical trial of immune checkpoint inhibition with controlled IL-12 gene therapy.