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

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

  • Sci Transl Med. 2019 Aug 14;11(505):eaaw5680. doi: 10.1126/scitranslmed.aaw5680.
E Antonio Chiocca 1 2,  John S Yu 3,  Rimas V Lukas 4 5 6,  Isaac H Solomon 7,  Keith L Ligon 7,  Hiroshi Nakashima 8,  Daniel A Triggs 8,  David A Reardon 2,  Patrick Wen 2,  Brittany M Stopa 8,  Ajay Naik 8,  Jeremy Rudnick 3,  Jethro L Hu 3,  Priya Kumthekar 4 5,  Bakhtiar Yamini 6,  Jill Y Buck 9,  Nathan Demars 9,  John A Barrett 9,  Arnold B Gelb 9,  John Zhou 9,  Francois Lebel 9,  Laurence J N Cooper 9 10
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. eachiocca@bwh.harvard.edu.
  • 2 Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • 3 Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 4 Ken and Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 5 Lou and Jean Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
  • 6 University of Chicago, Chicago, IL 60637, USA.
  • 7 Division of Neuropathology, Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 8 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 9 Ziopharm Oncology, Inc., One First Avenue, Parris Building 34, Navy Yard Plaza, Charlestown, Boston, MA 02129, USA.
  • 10 MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
PMID: 31413142 DOI: 10.1126/scitranslmed.aaw5680
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.

Figures
Products