INB-200: Phase I study and characterization of gene-modified autologous gamma delta (γδ) T cells in newly diagnosed glioblastoma multiforme (GBM).

2077 Background: Cell therapy for glioblastoma (GBM) holds promise but previous studies have not demonstrated durable responses or improved progression free survival (PFS). We provide updated findings from our assessment of any patients who completed treatment with drug-resistant immunotherapy (DRI) in newly diagnosed GBM. Methods: DRI combines the polyclonal upregulation of stress-antigens with concurrent local delivery of MGMT-modified γδ T cells, engineered to resist temozolomide (TMZ) driven lymphodepletion. The standard-of-care (SOC) chemotherapy TMZ induces transient upregulation of tumor-associated NKG2D-L stress antigens enabling the functional γδ T cells to identify and eradicate residual cancer cells during the period of maximum tumor vulnerability. Patients received 1 x 10 7 DRI cells/dose into the resection cavity with 150 mg/m 2 of IV TMZ on Day 1 of each maintenance cycle.17 patients received treatment, including 3 who received only a single dose (Cohort 1). 14 patients received repeated doses (3 to 6), (median age 64 (range: 33-75); 93% IDH-WT, 50% MGMT-unmethylated, 57% subtotal resection, KPS 80). 10 contemporaneously enrolled patients treated with SOC only (median age 67 (range: 49-77); 100% IDH-WT, 60% MGMT-unmethylated, 20% subtotal resection, KPS 80) were examined as a control cohort. Results: No DLTs, CRS, ICANS or treatment related deaths were reported. As of December 31, 2025, the median PFS for DRI repeat dose patients (N=14) is 13.0 months (m), vs. SOC control (N=10) of 6.6m (+97%) demonstrating prolonged disease control in newly diagnosed GBM. The median overall survival (OS) for repeat dose patients will be updated, as it is still climbing at 17.2m+ vs. SOC control of 13.2m. Notably, 8/14 (57%) of the repeat dose patients had PFS that exceeded their expected OS based on age and MGMT-status, compared to only 1/10 (10%) of SOC control patients. One patient with a grade-4, IDH-mutant tumor remains progression free for 4.6 years with no additional maintenance therapies. Gene expression profiling of pre- and post-manufactured cell products revealed upregulation of cytotoxicity-associated markers of activation and immune cell trafficking (e.g., IFN-g, GZMB, PRF1 ). Patient correlate analysis showed that CRS associated serum cytokines IL-6, IL-1B , CCL2 , and TNF-a were not increased over baseline during DRI + maintenance-phase TMZ. Peripheral γδ and total T cell levels, however, improved incrementally with each dose frequency cohort, suggesting an influence on systemic immune reconstitution through local DRI delivery. T cell persistence was demonstrated in recurrent GBM biopsies from patients that revealed significant γδ T cell infiltration and necrosis well beyond the final dose of TMZ and DRI γδ T cells. Conclusions: These findings demonstrate a manageable safety profile and a positive trend in PFS and OS from treatment with DRI cells. Clinical trial information: NCT04165941 .