First-in-human study of AAV6-NeuroD1 trans-differentiation therapy in recurrent malignant glioma.

2012 Background: Recurrent glioblastoma (GBM) has a median survival of less than 9 months. NeuroD1 is a neural transcriptional factor that can reprogram both glial cells and glioma cells into neuron-like cells, suppressing the proliferation of glioma cells and inducing cell death, extending the life span of animal models carrying glioblastoma. Therefore, scAAV6-NeuroD1 (NXL-004), a self-complementary adeno-associated virus 6 vector delivering NeuroD1, was developed to initiate a first-in-human study in patients with recurrent malignant glioma (ChiCTR2400080362). Methods: This is a single arm, open-label, dose-escalation study. The primary endpoint was safety, and the secondary endpoint was preliminary efficacy. Enrolled patients must have pathologically confirmed recurrent malignant glioma after standard therapy including surgery and chemoradiotherapy. NXL-004 was delivered intracavitary post-resection or intratumorally post-biopsy during surgery. Three dose levels (from 4.0x10 12 vg to 4.0x10 13 vg) were evaluated, using an accelerated dose escalation design. Up to two additional doses were allowed via an Ommaya reservoir at 2~4-week intervals after surgery. Results: 11 patients (median age 48.0, 81.8% male) were enrolled between 3/2024 and 6/2025. All patients had recurrent WHO grade 4 astrocytoma (10/11 IDH wild, 6/11 MGMT-unmethylated). Ten patients received repeat tumor resection plus intracavitary injection of NXL-004 (1 at low-dose, 3 at medium-dose, and 6 at high-dose), and one received biopsy plus intra-tumoral injection (low dose). All patients were included in the safety and efficacy analysis. No drug-related serious adverse event (SAE) or dose-limiting toxicities (DLT) was observed. All AEs related to NXL-004 were grade 1–2 (fever: 8/11; rash: 1/11; seizure: 1/11). Two grade 3 AEs (hemiplegia, meningitis) were reported but considered unrelated to the drug. Per RANO 2.0 criteria, the best overall response included 1 complete response (CR) and 5 stable disease (SD), yielding a disease control rate (DCR) of 54.5% (6/11). The median overall survival for all treated patients was 13.2 ± 2.0 months (95% CI: 9.3-17.1) from the first dose and 25.2 ± 1.2 months (95% CI: 23.0-27.5) from initial diagnosis. The first enrolled patient survived >18 months after dose. In the high-dose group, a higher DCR of 66.7% (4/6) was observed, with one patient achieving CR and one with SD surviving without progression >6 months (9 and 7 months, respectively, both ongoing). At a median follow-up of 9.0 months for this group, 5 patients were still alive, with 1 patient deceased (OS: 13.2 months). Conclusions: To our knowledge, this is the first clinical evidence of in vivo AAV-based trans-differentiation gene therapy for cancer treatment. NXL-004 showed favorable safety and encouraging efficacy, indicating that AAV-based cell reprogramming approach may represent a new modality for the treatment of glioma. Clinical trial information: ChiCTR2400080362.