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 Loewy, Kamal Chadha, Joseph Tringali, Laurence Cooper, Rimas V Lukas, 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 Loewy, Kamal Chadha, Joseph Tringali, Laurence Cooper, Rimas V Lukas
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 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 II clinical trial of immune checkpoint blockade with controlled IL-12 gene therapy (NCT04006119).
Keywords: clinical trial; controlled gene expression; gene therapy; glioblastoma; immunotherapy.
© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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Source: PubMed