Vaccination by homologous antigenic loading with DOC1021 as adjuvant therapy for glioblastoma: Phase I clinical trial results.

2014 Background: Glioblastoma is a devastating tumor for which median overall survival (mOS) remains 14-18 months despite aggressive standard of care (SOC) treatment. Clinical studies of dendritic cell (DC) vaccination for GBM have shown promise but have been largely inconclusive. DC homologous antigenic loading leverages p38MAPK and mTORC1 signaling cascades to initiate cDC1-like skewing of monocyte-derived DC, leading to potent downstream induction of tissue-homing cytolytic memory effector T cells. Here we report results of a completed phase I study for glioblastoma (IDH-wt). Methods: This clinical trial evaluated autologous DC vaccine DOC1021 prepared from mobilized peripheral blood mononuclear cells (PBMC), loaded with autologous tumor lysate and amplified tumor mRNA, and administered bilaterally near deep cervical lymph nodes. Three courses of vaccine every 2 weeks plus weekly peg-IFN were administered after completion of chemoradiation. Four dose levels from 3.5 x 10 6 to 3.6 x 10 7 total vaccine cells were tested. Patients with subtotal resection or tumor progression prior to vaccination were not excluded. Results: Sixteen newly diagnosed patients completed treatment, median age 61 years (range 47-73), 94% MGMT unmethylated, 25% subtotal resected. OS at 12-months was 88% compared to expected ~60% for SOC and 5 patients are still alive at 19-30 months of follow-up. Two recurrent glioblastoma patients were also treated and survived for 10-12 months. Most common AEs were mild flu-like symptoms and injection-site reactions, and there were no dose limiting toxicities. Analysis of post-vaccination PBMC indicated expansion of CD4 + (13/13 patients) and CD8 + (11/13) central memory T-cell compartments (p < 0.00006 and p < 0.003, respectively) as well as expansion of CD8 + CD127 + MPECs (12/13; p < 0.002). Among 3/3 patients analyzed by spatial transcriptomics, intense CD25 + foci correlating with co-expression of effector memory T-cell and migratory microglial markers were observed in post-vaccination but not pre-vaccination samples. For 8 patients who were observed rather than re-operated for worsening T1-weighted signal on MRI in the 23 weeks after vaccination, signal gradually resolved and GBM-specific mOS is not yet reached compared to 15.1 months for 8 patients who received reoperation despite comparable clinical characteristics, suggesting an immune-reactive microenvironment manifesting as pseudo-progression. Conclusions: DOC1021 combined with SOC is safe and potentially efficacious in this challenging population that included subtotal resections, pre-treatment progression and 15/16 MGMT unmethylated. A randomized phase II trial is being launched including criteria to avoid early re-operation for enhancing T1-weighted signal that may be pseudo-progression. Clinical trial information: NCT04552886 .