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Brain Tumor Gene Therapy Shows Early Promise in First-in-Human Trial

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Combination drug and immunotherapy treatment can extend survival in patients with gliomas, a highly aggressive form of brain cancer, suggests a new Phase 1, first-in-human trial. The study is published in The Lancet Oncology.

New treatments needed to tackle gliomas

Gliomas have a poor prognosis, and responses to treatments such as chemotherapy or radiation are limited. High-grade gliomas are particularly aggressive and have an extremely poor survival rate – median life expectancy sits at just over 14 months with the current standard of care and less than 5% of patients survive for 5 years following their diagnosis.

New treatments, such as gene therapies, are in development for gliomas. Some of these genetic therapies, called adenoviral vectors, use viruses to deliver genes into target cells so they produce the corresponding proteins.

In the current study, researchers combined two gene therapies previously shown to be effective in animal models to evaluate its safety and efficacy in a small number of glioma patients.

“Being able to move a novel therapy from bench to bedside in such a streamlined fashion is exciting and represents a tour-de-force in translational medicine,” said Dr. Oren Sagher, one of the study’s authors and a professor of neurosurgery at the University of Michigan.

Drug therapy and immunotherapy combined

The researchers tested a combination of genetic therapies centered around two proteins – herpes simplex virus type 1-thymidine kinase (HSV1-TK) and FMS-like tyrosine kinase 3 ligand (Flt3L). HSV1-TK is an enzyme that activates the antiviral drug valacyclovir – allowing the drug to kill dividing cells like those found in high-grade gliomas – while Flt3L is a cytokine and growth factor that recruits immune cells (typically absent from the brain) to kickstart the anti-cancer immune response.

The trial was designed to determine a dose that was safe and effective. The researchers recruited 18 patients with newly diagnosed, high-grade gliomas that had not yet undergone treatment. The patients underwent surgery to remove as much of their tumor as possible before the adenoviral therapy was injected into the tumor site. The patients then took two 14-day courses of oral valacyclovir that began at 1–3 days and 10–12 weeks post-treatment.

Of the 18 patients treated, 6 survived more than 2 years, 3 survived more than 3 years and one patient, who is still alive at the time of publication, has survived up to 5 years. Overall survival was 72% at 12 months and 39% at 24 months. The authors note that, although the study was not sufficiently powered to analyze survival, the observed median overall survival of 21.3 months is promising, given the historical figure of 14.6 months. Larger studies are required to investigate the possible effects on survival.

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The therapy was also hypothesized to remain active for up to a month, but the findings revealed that the HSV1-TK-expressing adenoviral vector was active for up to 17 months.

Finally, the low levels of toxicity that the patients experienced suggests that the highest dose used in this trial could be used in the design of future Phase 1B/2 clinical trials.

“Finally, after many years, we’re thrilled to report the results of testing this approach in human patients, obtaining results that will lead to better treatments for this group of brain tumor patients,” said Dr. Maria Castro, professor of neurosurgery at the University of Michigan and one of the senior authors of the study.

Reference: Umemura Y, Orringer D, Junck L, et al. Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial. Lancet Oncol. 2023;24(9):1042-1052. doi: 10.1016/S1470-2045(23)00347-9

This article is a rework of a press release issued by the University of Michigan. Material has been edited for length and content.