The Induction of Immunogenic Cell Death (ICD) During Maintenance Chemotherapy and Subsequent Multimodal Immunotherapy for Glioblastoma (GBM)

Abstract

The prognosis of Glioblastoma multiforme remains poor. Immunotherapy improved survival in a small fraction of patients. We studied the efficiency of multimodal immunotherapy as part of first line treatment for patients with GBM. Immunogenic Cell Death (ICD) was induced with Newcastle Disease Virus (NDV) and Modulated Electrohyperthermia (mEHT), and Dendritic Cell (DC) vaccinations loaded with autologous tumor proteins were performed. In a retrospective analysis of 60 adults, we detected 15 adults in whom NDV/mEHT were added at days 8/9/10 during Temozolomide Maintenance (TMZm) cycles, multimodal immunotherapy with NDV/mEHT/DC vaccinations were administered after TMZm, and further 3-day NDV/mEHT maintenance immunotherapy treatments were given thereafter. Median age was 60 years. Median Karnofsky was 90. There was no added toxicity due to immunotherapy. Median progression-free survival was 13 months (m). With a median follow up of 17m (ranging 4-30m), median overall survival was not reached, and estimated overall survival at 30m was 58% (95%CI: +27, -42). The detection of Apo10 protein epitope (Apo10) and Transketolase-like 1 (TKTL1) in monocytes, the mRNA expression level for PDL1 on circulating tumor cells, and the Th1/Th2 balance in CD4+ T cells showed a dynamic interaction between tumor cells and immune reactivity. The data suggest that the additional induction of ICD via NDV/mEHT during TMZm is beneficial in improving overall survival. While TMZm only targets dividing tumor cells, ICD targets dividing and non-dividing tumor cells. DC vaccination induces an antitumoral and anti-viral immune response which is maintained by the 3-day NDV/mEHT maintenance immunotherapy treatments.

Keywords: Newcastle disease virus; Modulated electrohyperthermia;
Glioblastoma; Immunogenic cell death; chemotherapy