OBJECTIVES: To provide a comprehensive overview of published clinical trials assessing gene therapies for the treatment of high-grade gliomas.

METHODS: We conducted a systematic literature review (SLR) following the PRISMA guidelines to identify clinical trials where gene therapies have been used as interventions for the treatment of high-grade gliomas in adults; oncolytic virotherapies were excluded. Searches were run on 15 May 2024 in MEDLINE, Embase, and Cochrane library (via OVID). Searches were limited to full publications in the English language. Publications were selected by two independent reviewers.

RESULTS: In total, 44 publications reporting on 41 trials were included in the SLR. The most commonly reported gene therapy was suicide gene therapy (SGT; n=20 [49%]), followed by immunomodulatory gene therapy (n=8 [20%]), gene target therapy (n=6 [15%]), antiangiogenic gene therapy (AGT; n=2 [5%]), and tumor suppressor gene therapy (n=1 [2%]). Four trials (10%) assessed combination therapies (SGT and immunomodulatory gene therapies). Most trials were Phase I (n=21 [51%]) and only six (15%) were randomized controlled trials (RCTs). Of these, five reported on SGTs in patients with recurrent high-grade gliomas (n=3) or in newly diagnosed glioblastoma (n=2), with a sample size ranging from 44 to 403. Three RCTs found no improvement in overall survival (OS) with SGT compared with the standard of care (SOC), whereas two reported a statistically significant increase. One RCT focused on AGT in patients with recurrent glioblastoma, with a sample size of 256. In this trial, AGT did not improve OS compared with SOC.

CONCLUSIONS: The majority of the published trials included in this SLR reported on SGT. Only 15% of studies were RCTs and, in most cases, OS did not differ between gene therapies and SOC.