Author:

Keywords:

Dendritic cell-based tumor vaccination, Immunotherapy, High-grade glioma

Abstract:

In spite of full, state-of-the-art oncological therapy, including maximal safe surgical resection, external beam radiotherapy and chemotherapy, the prognosis of glioblastoma multiforme (GBM) remains poor with a median survival of 14.6 months. Notwithstanding this maximal treatment, relapse is universal. At time of recurrence, prognosis is even worse and virtually all patients die within 18 months after relapse. There is a clear need for well-tolerated long-term treatments that are tumor-specific and able to kill all (residual) tumor cells that infiltrate in the adjacent areas of the brain. The immune system provides us with some promising tools in that regard, and therefore we have investigated the integration of dendritic cell (DC)-based immunotherapy in the current therapeutic concepts, both in newly diagnosed and relapsed GBM patients.First, we have implemented immunotherapy for the treatment of patients with relapsed high-grade glioma (HGG), as a stepwise process using a cohort-comparison study concept (HGG-IMMUNO-2003). We slightly modified the original RTOG RPA classification, a known model to define prognostic classes based on treatment and pre-treatment prognostic variables, and made it applicable to patients treated in this study. In this heterogeneous group of patients, we could define simple, clinically relevant, prognostic classes using this modified RTOG RPA model. Also, we found long-term survivors after relapse in classes III and IV, which is a remarkable clinical finding, comparing favorably to almost all other trials in (multi-)relapsed patients with HGG. Based on the already published importance of age in DC vaccination in the patients with relapsed HGG, we analyzed the results in 45 children (18 years and younger) with a recurrent malignant brain tumor, who were treated with autologous DC-based immunotherapy (HGG-IMMUNO-2003). We could demonstrate the clinical feasibility of this approach without major adverse events, even in young children. HGG seem to respond more favorably to vaccination than ependymoma and medulloblastoma/primitive neuro-ectodermal tumor, and – for atypical teratoid-rhabdoid tumor – the addition of immunotherapy to radio- and chemotherapy might be beneficial. Although preliminary, and derived from a heterogeneous patient group, our results on DC-based vaccination support testing of the integration of this innovative immunotherapy approach in new treatment protocols for HGG and atypical teratoid-rhabdoid tumor.Next, we integrated DC-based immunotherapy in the standard primary treatment of GBM, consisting of maximal safe surgical resection, radiotherapy and temozolomide (TMZ) chemotherapy. In 8 pilot, adult newly-diagnosed GBM patients, tumor vaccination proved to be feasible and well tolerated. The survival data were used to power the phase I/II HGG-2006 trial for patients with newly-diagnosed GBM, in which 77 patients were included. Median overall survival (OS) based on intent-to-treat analysis was 18.3 months, which compares favorably to the survival data reportedby Stupp et al. with a median OS of 14.6 months. Survival seems to be improved especially in the patients belonging to EORTC RPA classes III and IV. The integration of immunotherapy within the standard postoperative therapy for patients with a newly diagnosed GBM is based on the presumed mutually beneficial effect of the conventional treatment strategies and immunotherapy. It is hypothesized that the combination of radiotherapy, chemotherapy and immunotherapy could potentiate the cumulative antitumoral activity, when applied in a well designed strategy. For this radio-chemo-immunotherapy, we provide feasibility data in terms of clinical responses, as well as an acceptable QOL.Finally, we addressed the issue of immune monitoring in vaccinated, newly-diagnosed GBM patients. Both in the pilot and HGG-2006 trial, we applied flow cytometry on peripheral blood as immune monitoring tool to assess the induction and/or maintenance of vaccine-induced antitumoral immunity in the close temporal relationship with radiochemotherapy. For this, we first validated IL-7 receptor alpha subunit (CD127) dim expression as a marker for human Treg cells, since these cells have claimed a very prominent role in tumor immunology as potential suppressors of immune responses. Thus, monitoring of Treg cells is essential in patients treated with immunotherapy. ‘Immunological profiles’ based on flow cytometry, were compared to clinical outcome, but no clear correlation between immunological and clinical responses was found. A possible explanation for this lack in correlation might be that the peripheral immune status does not mirror the immune responses that occur in the tumor itself. Therefore, we established a baseline phenotypical characterization of brain tumor-infiltrating cells, which we compared to the immune status of the patient as measured in the peripheral blood. Preliminary results seem to indicate in fact, that the peripheral immune status does not mimic the intratumoral immune reaction. How these findings relate to immune monitoring in vaccinated patients has to be further elucidated, but one might argue that peripheral immune monitoring tools are not well suited for the full monitoring of the immune response against these tumors.