Combined immunotherapy with controlled interleukin-12 gene therapy and immune checkpoint blockade in recurrent glioblastoma: An open-label, multi-institutional phase I trial

Abstract

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).

Immune cell regulation in stem cell niche contacting glioblastomas

“…Of the 38 clusters, 17 were statistically enriched in immune cells from C-GBM patients, and 17 were enriched in cells from NC-GBM patients. Four clusters (19, 26, 32, 34) were not statistically enriched in either cohort ( Figure 1g, Figure 1h, Supplementary Figure 1 ). Taken together, these data highlight extensive differences in the immune composition of GBM tumors and suggest that while immune infiltration occurs in both C-GBM and NC-GBM, the relative composition of the immune cell fraction in ventricle contacting tumors is distinct from that of ventricle non-contacting tumors.…”

“…While immune-targeted drugs have proven effective at generating antitumor immunity towards peripheral solid tumors and in some cases mediate complete tumor regression, the same efficacy has not been demonstrated in neurologic tumors (NCT02017717, NCT02667587) (23,24). Early work using immunotherapeutic strategies has, in fact, demonstrated some capacity to elicit antitumor immunity, yet these approaches have not improved GBM outcomes (25)(26)(27), highlighting a need for novel, straightforward approaches, such as MRI-guided regional tumor position, to identify appropriate immune targets and patient cohorts to optimize therapeutic benefit.…”

Immunotherapy in Glioblastoma: Current Approaches and Future Perspectives

“…Interleukin 12 (IL-12) is a cytokine with anticancer activity, but limited application as a systemic therapeutic agent due to severe toxicity [84]. A ligand-inducible expression switch called the RheoSwitch Therapeutic System ® (RTS ® ) was designed for local control of IL-12 production within the tumor microenvironment [85]. The system relies on use of activator ligand velemidex with delivery of IL-12 transgene achieved by use of an adenoviral vector Ad-RTS-hIL-12 [85].…”

Innovating Strategies and Tailored Approaches in Neuro-Oncology

“…This provided the rationale for a combinatorial approach testing the association of the Ad-RTS-hIL-12 gene therapy with the anti-PD1 nivolumab [ 149 ]. In the phase I trial, the combination displayed no additional toxicity compared to IL12 gene monotherapy [ 149 ], and a phase II trial (NCT04006119, Table 2 ) has been completed, results are awaited. Gene therapy can be used also to target protumoral cells in the tumor microenvironment.…”

“…Re-resected tumors displayed increased CD8+ lymphocytes, mostly expressing PD1. This provided the rationale for a combinatorial approach testing the association of the Ad-RTS-hIL-12 gene therapy with the anti-PD1 nivolumab [149]. In the phase I trial, the combination displayed no additional toxicity compared to IL12 gene monotherapy [149], and a phase II trial (NCT04006119, Table 2) has been completed, results are awaited.…”