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

E. Antonio Chiocca, Arnold B. Gelb, Clark C. Chen, Ganesh Rao, David A. Reardon, Patrick Y. Wen, Wenya Linda Bi, Pierpaolo Peruzzi, Christina Amidei, Dan Triggs, Leah Seften, Grace Park, James Grant, Kyla Truman, Jill Y. Buck, Nira Hadar, Nathan Demars, John Miao, Taylor Estupinan, John LoewyKamal Chadha, Joseph Tringali, Laurence Cooper, Rimas V. Lukas

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 I trial in rGBM subjects (NCT03636477) accrued 21 subjects 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). 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 IFNγincreased 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 II clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).

Original languageEnglish (US)
Pages (from-to)951-963
Number of pages13
JournalNeuro-Oncology
Volume24
Issue number6
DOIs
StatePublished - Jun 1 2022

Bibliographical note

Funding Information:
The clinical trial was sponsored by Ziopharm Oncology, Inc. E.A.C. received support from grants 2P01CA163205 and CA069246-20 from the National Institutes of Health.

Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Keywords

  • clinical trial
  • controlled gene expression
  • gene therapy
  • glioblastoma
  • immunotherapy

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