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

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.