Intracranial Injection of Investigational Ex Vivo Expanded and Activated Gamma-Delta T Cells Engineered With a Methylguanine-DNA Methyltransferase–Expressing Lentivector in Patients With Primary Glioblastoma
Journal of Clinical Oncology, 2026
Nabors L., Lobbous M., Han X., Fiveash J., Di Stasi A., Rochlin K., Oster R., Pillay T., Miller R., Chandrashekar D., ter Haak M., Ho W., Lamb L.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology Immunotherapy | Pathophysiology | Plasma |  Olink Target 48 |
Abstract
PURPOSE
We developed a novel approach to treat newly diagnosed glioblastoma (GBM) using genetically modified gamma-delta (γδ) T cells following the forced upregulation of stress-associated targets on tumor cells. We leveraged the temozolomide (TMZ)-induced activation of the DNA damage response pathway to transiently upregulate the natural killer ligand (NKG2D-L) targets on GBM. Manufactured γδ T cells are engineered to be resistant to alkylating chemotherapies, including TMZ, through insertion of a methylguanine-DNA methyltransferase (MGMT)–expressing lentivector (DeltEx drug-resistant immunotherapy—DRI).
METHODS
A total of 23 patients were enrolled, and 13 were treated (62% male; median age 66 years [range, 21-75]; 92% isocitrate dehydrogenase wild type (IDH-WT), 54% MGMT unmethylated, 46% subtotal resection). Cohorts 1, 2, and 3 received 1, 3, or up to 6 doses, respectively (1 × 10 7 DRI cells/dose), using a Rickham catheter, which was placed into the resection cavity. The DRI cells were dosed in combination with 150 mg/m 2 intravenous (IV) TMZ once per day on Day (D) 1 of each maintenance cycle, which was followed by 4 days of oral TMZ.
RESULTS
No dose-limiting toxicities were seen nor were any occurrences of cytokine release syndrome (CRS) or neurotoxicity (immune effector cell–associated neurotoxicity syndrome) observed. The median follow-up of patients who received DRI γδ T cells was 15.6 months. For Cohort 1 patients who received a single dose of DRI γδ T cells, the median progression-free survival (mPFS) was 8.0 months; the median PFS was 9.9 months for all patients and 16.1 months for patients who received repeated doses in Cohorts 2 and 3. The median overall survival for all patients was 15.6 months.
CONCLUSION
To date, all patients had manageable toxicity with outpatient treatment and a continued encouraging trend in outcomes from repeated investigational treatments with intracranially delivered, longitudinal DRI γδ T cells.