Multimodal immunotherapy integrated into standard therapy for GBM: learning from clinical practice

There is a high demand for innovative treatment strategies for children and adults with malignant glioma. The ultimate aim is to prolong long-term overall survival with good quality of life. To reach this goal, immunotherapy is emerging. While the immune system is very complex, early phase immunotherapy clinical trials restrict to single modes of action and point to the reproducible conclusion about feasibility without major toxicity and perspective towards potential activity. Personalized multimodal immunotherapy using combinations of modes of action is however performed outside clinical trial, but might generate insights to design future treatment plans. At IOZK we are working on the combination of oncolytic virus therapy with Newcastle Disease Virus (NDV), modulated electrohyperthermia (mEHT), autologous DC vaccines and immunomodulatory strategies.

Both NDV and mEHT are inducers of immunogenic cell death (ICD), which we could demonstrate by an increase of tumor-derived epitopes during serial measurements in a test called “PanTum detect”, based on the Epitope Detection in Monocytes (EDIM) technology. Body-derived neutralizing mechanisms of NDV upon repetitive administration have been demonstrated and have let to injection of NDV as a bolus shot aimed to induce a short but high peak concentration thereby allowing tumor infection (and intratumoral further replication) before systemic neutralization.

Thirty eight DIPG children with median age 5.5y (range 2 – 19y) were treated with multimodal immunotherapy, 26 of them as part of primary treatment (DIPGprim), before or after radiotherapy, and 12 at time of progressive disease after first line treatment (DIPGprog). 83% of DIPGprim children had a Lansky score > 70. At start of immunotherapy, 31% of children had deficient IFN-g expression in the CD4+ T cells. Diminished NK function was observed in 77%. Data were fixed at 01/10/2017. The repetitive NDV infusions and modulated electrohyperthermia, and the production and administration of the DCs were feasible. No major toxicity was observed. We detected the increase of GBM antigen cross-reacting IFN-g-producing T cells in those patients that could be immunomonitored. Median PFS of DIPGprim children was 8.26 m. Rescue after progression was mainly re-irradiation. Median OS was 14.23 months. 18 m OS was estimated as 28% (asymmetrical 95%CI: +21.34, -18.15). Median OS of the 12 DIPGprog children calculated from last event prior to immunotherapy was 3.14 m. Multimodal immunotherapy might be of help for DIPG children as part of first-line treatment.

In a retrospective analysis of 60 adults with primary diagnosis of GBM, we detected 15 adults in whom NDV/mEHT were added at days 8/9/10 during TMZ maintenance (TMZm) cycles, multimodal NDV/mEHT/DC vaccinations were administered after maintenance chemotherapy, and further 3-day NDV/mEHT maintenance immunotherapy were given thereafter. Database was fixed at 15/03/2018. Median age was 60 years (ranging 37 – 67y). KPI was 90 (ranging 60 – 100). There was no added toxicity due to ICD during TMZm, or later during multimodal NDV/mEHT/DC vaccinations. Median PFS was 13 m. With a median follow up of 17 m (range 4 – 30 m), median OS was not reached, and estimated OS at 30 m was 58% (95%CI: +27, -42). Apo10 and TKTL1 detection in monocytes and mRNA expression for PDL1 on circulating tumor cells showed a dynamic interaction between tumor cells and immune reactivity. The data suggest that addition of NDV/mEHT for ICD during TMZm might be beneficial in controlling disease progression and improving OS. While TMZm only targets dividing tumor cells most when MGMT is methylated, ICD via NDV/mEHT targets both dividing but also non-dividing tumor cells. Finally the active specific immunotherapy induces an antitumoral and anti-viral immune response against NDV/mEHT targeted tumor cells which is maintained by NDV/mEHT maintenance immunotherapy. The data can be of use when considering new treatment protocols for children with GBM.