Improvement of dendritic cell therapy in glioblastoma multiforme WHO 4 by Newcastle disease virus.
ABSTRACT
Background: Glioblastoma multiforme (GBM, WHO grade 4 glioma) is an aggressive disease with an unfavorable prognosis. The current first line treatment comprises radical operation and radiotherapy combined with temozolomide chemotherapy. The reported median overall survival time after primary diagnosis is less than 15 months. After failure of first-line therapy there is currently no effective therapy, and side effects from further treatments may potentially impair quality of life. We report that immunotherapy with monocyte-derived dendritic cells (MoDC) combined with oncolytic Newcastle Disease Virus (NDV) can improve the efficacy of dendritic cell based immune therapy for relapsed GBM.
Methods: After isolating monocytes from peripheral blood of n=37 patients with stage IV GBM who failed first-line radio-chemotherapy (PFI: 8 months), MoDC were generated using standard protocols. In 19 patients, NDV was added to the MoDC on day 5. These patients were also pretreated with an infusion with NDV one day before vaccination. The MoDC were harvested on day 7 of culture and administered to the patients intradermally.
Results: Improvement of the clinical response was observed in patients, who received combination of NDV with MoDC vs. MoDC alone (47% vs. 11%). The median survival after onset of DC-therapy was 3 months with MoDC alone and 10 months (23 months after primary diagnosis) in combination with NDV. The 1- year-survival rates after onset of DC therapy were 6% and 32%, respectively. The therapy was well tolerated without any major side effects. IFN-gamma Elispot analyses from patients who received NDV injections and NDV-primed MoDC show that MoDC primed with NDV can induce a specific CD4 and CD8 T-cell response against NDV whereas healthy donors show no specific T-cell response.
Conclusions: The efficacy of dendritic-cell based therapy for GBM can be improved by combination with NDV and may prolong overall survival of patients after failure of first-line therapy. For a first time we demonstrate that NDV primed MoDC induces a NDV specific T-cell response in humans, which may lead to in-vivo lysis of NDV-infected tumor cells.