INB-200: Phase 1 study of gene-modified autologous gamma-delta (γδ) t cells in newly diagnosed glioblastoma multiforme (GBM) patients receiving maintenance temozolomide (TMZ).

2007 Background: Recent cell therapy and CAR-T initiatives for GBM have shown initial responses but durability has been disappointing. We developed a novel approach to treat newly diagnosed GBM using innate γδ T cells following forced upregulation of tumor stress-associated targets. Methods: We leveraged the TMZ-induced activation of the DNA damage response (DDR) pathway to transiently upregulate NKG2D-L targets on GBM. Co-administration of TMZ chemotherapy with γδ T cells engineered for TMZ resistance by insertion of a methylguanine-DNA methyltransferase (MGMT)-expressing lentivector (DeltEx Drug Resistant Immunotherapy – DRI) enables the targeting of residual GBM cells during the standard-of-care Stupp regimen. A total of 23 patients were enrolled, with 13 treated and (62% male; median age 66 (range: 21-74); 92% IDH-WT, 54% MGMT-unmethylated). Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 10 7 DRI cells/dose) into the resection cavity with 150 mg/m 2 of IV TMZ on Day (D) 1 of each Stupp regimen maintenance cycle. Results: No Dose limiting toxicities (DLTs) were seen nor were occurrences of cytokine release syndrome (CRS) or neurotoxicity (ICANS). Most common adverse events were related to underlying TMZ and Stupp regimen. As of January 24, 2025, median follow-up is 16.9 months (m). The median PFS for patients is 8.3m for those who received a single dose of INB-200, 9.9m for all patients (a 44% increase over the 6.9m mPFS of the Stupp) and 14.0m for patients who received repeated doses, an 102.4% improvement over Stupp and 69% over single dose patients. A patient with IDH mutant tumor remains progression free for almost 44 months and one with MGMT-unmethylated tumor for 18 months. Biopsy specimens from three patients are available with general immune activation having been demonstrated. Conclusions: To date all patients had manageable toxicity with outpatient treatment and a continued encouraging trend in longer PFS from treatment with DRI γδ T cells. Clinical trial information: NCT04165941 . Subject Age/Sex IDH/Methylation Resection Dose level TMZ Maint. Cycles Received Response PFS (mos) OS (mos) 001 69/M IDH-WT, MGMT-unmethylated Total 1 5 SD 8.3 15.6 003 75/F IDH-WT, MGMT-methylated Total 1 6 SD 11.9 17.7 004 21/F IDH-WT, MGMT-unmethylated Total 1 3 SD 7.4 9.6 007 75/M IDH-WT, MGMT-unmethylated Total 2 2 Un-evaluable - 5.1 009 32/M IDH-mutant, MGMT-methylated Total 2 12 SD 43.7+ 011 56/F IDH-WT, MGMT-methylated Total 2 6 SD 22.2 28.6 014 73/F IDH-WT, MGMT-unmethylated Subtotal 2 6 SD 8.7+ 8.7 without progression 015 73/M IDH-WT, MGMT-methylated Subtotal 3 5 SD 7.1 11.8 017 74/F