Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma: Results of a phase 1 trial.
Adrenal Cortex Hormones
/ pharmacology
Adult
Aged
Dexamethasone
/ pharmacology
Female
Gene Expression Regulation
/ drug effects
Genetic Therapy
/ methods
Glioma
/ blood
Heterocyclic Compounds, 4 or More Rings
/ therapeutic use
Humans
Interferon-gamma
/ blood
Interleukin-12
/ blood
Kaplan-Meier Estimate
Male
Middle Aged
Neoplasm Recurrence, Local
/ genetics
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
14 08 2019
14 08 2019
Historique:
received:
06
01
2019
accepted:
01
07
2019
entrez:
16
8
2019
pubmed:
16
8
2019
medline:
28
7
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31413142
pii: 11/505/eaaw5680
doi: 10.1126/scitranslmed.aaw5680
pmc: PMC7286430
mid: NIHMS1559028
pii:
doi:
Substances chimiques
Adrenal Cortex Hormones
0
Heterocyclic Compounds, 4 or More Rings
0
veledimex
0
Interleukin-12
187348-17-0
Dexamethasone
7S5I7G3JQL
Interferon-gamma
82115-62-6
Banques de données
ClinicalTrials.gov
['NCT02026271']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NINDS NIH HHS
ID : R01 NS110942
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA136937
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA069246
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA221747
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA163205
Pays : United States
Informations de copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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