Research ArticleCancer

Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial

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Science Translational Medicine  14 Aug 2019:
Vol. 11, Issue 505, eaaw5680
DOI: 10.1126/scitranslmed.aaw5680

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Think globally, treat locally

The antitumor cytokine interleukin-12 cannot be used as a systemic treatment because of excessive toxicity. To safely take advantage of its beneficial properties, Chiocca et al. applied a two-part strategy for patients with recurrent aggressive glioma. The patients first received gene therapy with a vector encoding human interleukin-12, injected into the tumor resection cavity. Subsequently, the patients were treated with a compound called veledimex, activating interleukin-12 production. Although some interleukin-12 was found in the patients’ circulation, intracranial injection of the gene therapy appeared to be beneficial, showing limited toxicity and promising signs of antitumor immune response.

Abstract

Human interleukin-12 (hIL-12) is a cytokine with anticancer activity, but its systemic application is limited by toxic inflammatory responses. We assessed the safety and biological effects of an hIL-12 gene, transcriptionally regulated by an oral activator. A multicenter phase 1 dose-escalation trial (NCT02026271) treated 31 patients undergoing resection of recurrent high-grade glioma. Resection cavity walls were injected (day 0) with a fixed dose of the hIL-12 vector (Ad–RTS–hIL-12). The oral activator for hIL-12, veledimex (VDX), was administered preoperatively (assaying blood-brain barrier penetration) and postoperatively (measuring hIL-12 transcriptional regulation). Cohorts received 10 to 40 mg of VDX before and after Ad–RTS–hIL-12. Dose-related increases in VDX, IL-12, and interferon-γ (IFN-γ) were observed in peripheral blood, with about 40% VDX tumor penetration. Frequency and severity of adverse events, including cytokine release syndrome, correlated with VDX dose, reversing promptly upon discontinuation. VDX (20 mg) had superior drug compliance and 12.7 months median overall survival (mOS) at mean follow-up of 13.1 months. Concurrent corticosteroids negatively affected survival: In patients cumulatively receiving >20 mg versus ≤20 mg of dexamethasone (days 0 to 14), mOS was 6.4 and 16.7 months, respectively, in all patients and 6.4 and 17.8 months, respectively, in the 20-mg VDX cohort. Re-resection in five of five patients with suspected recurrence after Ad–RTS–hIL-12 revealed mostly pseudoprogression with increased tumor-infiltrating lymphocytes producing IFN-γ and programmed cell death protein 1 (PD-1). These inflammatory infiltrates support an immunological antitumor effect of hIL-12. This phase 1 trial showed acceptable tolerability of regulated hIL-12 with encouraging preliminary results.

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