Tumor stem cell RNA-leaded dedritic cell vaccine for recurrent glioblastoma: a phase 1 trail.

Objective: To evaluate the feasibility and safety of administering brain tumor stem cell (BTSC) mRNA-loaded dendritic cells (DC) to patients with recurrent GBM. Background: BTSC CD133+ contribute to GBM propagation and are associated with chemo-radiation resistance, but their susceptibility to immunotherapy is not known. Here, we attempt to generate BTSC RNA-loaded DC vaccination as a novel GBM immunotherapy. Design/Methods: Patients with first supratentorial GBM recurrence ≥8 weeks after radiation underwent resection followed by leukapheresis to generate CD133+ BTSC RNA-loaded DCs. If BTSC RNA could not be sufficiently obtained, total tumor RNA (ttRNA) was used. The first 3 vaccines were administered at weekly intervals. An escalating total dose of mRNA-loaded DCs (2×106, 5×106, and 2×107 per vaccination) was evaluated to establish a MTD and DLT. Subsequent vaccines were given monthly until progression. Following first participant enrollment, bevacizumab was FDA approved for recurrent GBM, and the study was amended to add concurrent bevacizumab. Results: Fifty-four subjects were enrolled; 21 were ultimately assessed on protocol. Fourteen subjects withdrew before attempt to obtain RNA: patient withdrawal (3), disease progression (2), death (1), adverse events (4), and unavailable tumor specimen (4). One participant was not evaluated due to a protocol violation. Among the remaining 39 patients, success rate for RNA isolation was 71.8%. Seven of the 28 patients with RNA did not receive treatment: disease progression (2), death (1), AEs (2), QC failure, and patient withdrawal (1). Ten patients received BTSC RNA-loaded DCs and 11 received ttRNA-loaded DCs. No DLT was observed. The most common AE was mild fatigue (43%). Nine patients experienced grade I or II hematologic toxicities. PFS from first vaccination was 3.2 months (95.0% CI:1.8–7.2) and OS was 11 months (95.0% CI:8.2–14.8). Conclusions: ttRNA or BTSC RNA-pulsed DCs in combination with bevacizumab is feasible, safe and well-tolerated. Immune-monitoring analysis will be presented.

Duke Scholars

Author Katherine Barnett Peters Neurosurgery, Neuro-Oncology

Author Henry Seth Friedman Neurosurgery, Neuro-Oncology

Author James Emmett Herndon II Biostatistics & Bioinformatics, Division of Biostatistics

Author Qi-Jing Li Integrative Immunobiology

Author John Howard Sampson Neurosurgery