In a single-center, phase I, first-in-human trial reported in The Lancet Oncology, Yoshie Umemura, MD, and colleagues investigated treatment with the combination of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in adults with primary high-grade glioma.
As stated by the investigators: “High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing [HSV1-TK and Flt3L] in patients with high-grade glioma.”
Yoshie Umemura, MD
Study Details
In the study, 18 patients (aged 18 to 75) who had not received prior treatment underwent resection at the University of Michigan Medical School, Michigan Medicine, between April 2014 and March 2019. The study included six escalating doses of Ad-hCMV-TK and Ad-hCMV-Flt3L, with three patients per dose level. The mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors was administered freehand into the walls of the resection cavity; the total injection was 2 mL distributed as 0.1 mL per site across 20 locations. Patients then received two 14-day courses of valacyclovir at 2 g three times per day at 1 to 3 days and 10 to 12 weeks after vector administration and standard upfront chemoradiotherapy. The primary outcome measure was safety; overall survival was a secondary endpoint.
Key Findings
No dose-limiting toxicity was observed for the adenoviral vectors, and the maximum tolerated dose was not reached.
Adverse events considered at least possibly related to adenoviral vector treatment across all treatment groups were one case each of grade 1 or 2 seizure, maculopapular rash, dyspepsia, headache, dizziness, hallucinations, increased creatinine, and confusion. Grade 3 treatment-related adverse events consisted of one case each of seizure, encephalopathy, and acute kidney injury; no grade ≥ 4 events were reported. The most common serious grade 3 or 4 adverse events, irrespective of cause, were wound infection (four events in two patients) and thromboembolic events (five events in four patients). Adverse events led to death in one patient, from respiratory failure considered unrelated to treatment.
Among all patients, median progression-free survival was 9.9 months (95% confidence interval [CI] = 7.3–13.3 months). Median overall survival was 21.3 months (95% CI = 11.1–26.1 months), with rates at 12 and 24 months of 72.2% (95% CI = 45.6%–87.0%) and 38.8% (95% CI = 17.5%–60.0%). At the time of analysis, three patients were alive at 3 years, two were alive at 4 years, and one was alive at 59 months after enrollment.
The investigators concluded: “The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase Ib/II clinical trial.”
Pedro R. Lowenstein, MD, PhD, of the Department of Neurosurgery, the University of Michigan Medical School, Ann Arbor, is the corresponding author of The Lancet Oncology article.
Disclosure: The study was funded by the Phase One Foundation; Board of Governors at Cedars-Sinai Medical Center, Los Angeles; and the Rogel Cancer Center at the University of Michigan. For full disclosures of the study authors, visit thelancet.com.
