Abstract
Background
VXM01 consists of the attenuated Salmonella Typhi strain Ty21a carrying a plasmid encoding vascular endothelial growth factor receptor 2 (VEGFR2). The bacterium serves as a vector to deliver the plasmid into the Peyer’s patches via the oral route of administration. The vaccine elicits a systemic T-cell response targeting VEGFR2. This trial examined safety and tolerability, clinical and immunogenic responses to VXM01 after at least four vaccinations at 106 or 107 colony-forming units in patients with progressive glioblastoma who have failed at least radiochemotherapy with temozolomide and who are candidates for a reoperation.
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 during the tumor follow-up period after surgery. Follow-up was done by weekly safety laboratories and physical examinations in the treatment period and 4-weekly thereafter, MRI, T-cell immunomonitoring in the peripheral blood by IFN-γ ELISpot, 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 129 adverse events, mostly unrelated to VXM01, were observed after a median of 7.5 doses per patient. ELISpot analysis showed a detectable VEGFR2-specific T cell response in 7 out 12 (58%) patients measured. In the observation period up to 2 years, seven patients are alive and survived for more than 12 months after initiation of treatment. 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 measured arguing for combination of VXM01 with an anti-PD-L1 checkpoint inhibitor. A strong partial response was observed in one patient under VXM01 monotherapy, further improved in a complete response after addition of nivolumab to VMX01.
Conclusion
VXM01 was safe and produces detectable specific peripheral immune responses and increased T-cell infiltration 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 avelumab in 30 patients with relapsed glioblastoma has been launched.