TY - JOUR
T1 - Regulatable interleukin-12 gene therapy in patients with recurrent high-grade glioma
T2 - Results of a phase 1 trial
AU - Chiocca, E. Antonio
AU - Yu, John S.
AU - Lukas, Rimas V.
AU - Solomon, Isaac H.
AU - Ligon, Keith L.
AU - Nakashima, Hiroshi
AU - Triggs, Daniel A.
AU - Reardon, David A.
AU - Wen, Patrick
AU - Stopa, Brittany M.
AU - Naik, Ajay
AU - Rudnick, Jeremy
AU - Hu, Jethro L.
AU - Kumthekar, Priya
AU - Yamini, Bakhtiar
AU - Buck, Jill Y.
AU - Demars, Nathan
AU - Barrett, John A.
AU - Gelb, Arnold B.
AU - Zhou, John
AU - Lebel, Francois
AU - Cooper, Laurence J.N.
N1 - Funding Information:
This paper is dedicated to the memory of the patients and their families who participated in this trial. We thank J. W. Ragheb at NeoGenomics Inc. for pathological review of tumor samples. We thank the study participants and their families for participation, as well as the research staff for hard work on the trial, and A. Gwosdow for editorial support. The clinical trial and correlative studies were funded by Ziopharm Oncology Inc. and by the National Institutes of Health (NIH) grant numbers 2P01CA163205 and CA069246-20 to E.A.C.
Publisher Copyright:
© 2019 The Authors.
PY - 2019/8/14
Y1 - 2019/8/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071282213&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071282213&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aaw5680
DO - 10.1126/scitranslmed.aaw5680
M3 - Article
C2 - 31413142
AN - SCOPUS:85071282213
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 505
M1 - eaaw5680
ER -