Background: VXM01 consists of an attenuated Salmonella typhi Ty21a carrying a plasmid encoding for vascular endothelial growth factor receptor (VEGFR)-2. The bacterium is a vector via the oral route of administration carrying the plasmid into the Peyer’s plaques. The vaccine elicits a systemic T-cell response targeting VEGFR-2. This trial examined safety and tolerability, clinical and immunogenic response to VXM01 after at least four vaccinations [10⁶ or 10⁷ colony-forming units (CFU)] in patients with progressive glioblastoma who have failed at least radiochemotherapy with temozolomide. Methods: Patients with progressive operable glioblastoma were subjected to VXM01 in one oral administration each on day 1, 3, 5, and 7. In addition, VXM01 was allowed to be administered in 4-weekly single doses every 4 weeks during the tumor follow-up period after surgery. Follow-up was done by weekly safety laboratories and physical examinations in the treatment period and 12-weekly thereafter T-cell immunomonitoring in the peripheral blood, and brain tumor immunohistochemistry. Results: Fourteen patients have been treated with VXM01. Three out of them with additional nivolumab. Surgery has been performed in eight patients. Under VXM01 treatment 119 adverse events, mostly unrelated to VXM01, were observed after a median of 8 doses per patient. ELISpot analysis showed a detectable VEGFR-2 specific T cell response in 7 out 12 (58%) patients measured. In the observation period of up to 20 months 7 patients are alive, 5 out of them survived for more than one year, 2 patients are ongoing at month 10. In one patient there was an objective and durable T1 response. Survival seemed to be correlated with a higher CD8/Treg ratio in progressive and primary tumor, which further increased after VXM01 treatment. In patients with prolonged survival a decrease in intratumoral PD-L1 was observed arguing for combination of VXM01 with an anti-PD-L1 checkpoint inhibitor. Conclusions: VXM01 was safe and produces detectable specific peripheral immune responses as well as CD8/Treg ratio increase in post-vaccine tumor tissue. There was one patient with an objective response. As a next step, a combination study of VXM01 and anti-PD-L1 checkpoint inhibitor has been launched. Clinical trial information: NCT02718443