Immunological analysis of phase II glioblastoma dendritic cell vaccine (Audencel) trial: immune system characteristics influence outcome and Audencel up-regulates Th1-related immunovariables

Abstract

Audencel is a dendritic cell (DC)-based cellular cancer immunotherapy against glioblastoma multiforme (GBM). It is characterized by loading of DCs with autologous whole tumor lysate and in vitro maturation via “danger signals”. The recent phase II “GBM-Vax” trial showed no clinical efficacy for Audencel as assessed with progression-free and overall survival in all patients. Here we present immunological research accompanying the trial with a focus on immune system factors related to outcome and Audencel’s effect on the immune system. Methodologically, peripheral blood samples (from apheresis before Audencel or venipuncture during Audencel) were subjected to functional characterization via enzyme-linked immunospot (ELISPOT) assays connected with cytokine bead assays (CBAs) as well as phenotypical characterization via flow cytometry and mRNA quantification. GBM tissue samples (from surgery) were subjected to T cell receptor sequencing and immunohistochemistry. As results we found: Patients with favorable pre-existing anti-tumor characteristics lived longer under Audencel than Audencel patients without them. Pre-vaccination blood CD8+ T cell count and ELISPOT Granzyme B production capacity in vitro upon tumor antigen exposure were significantly correlated with overall survival. Despite Audencel’s general failure to induce a significant clinical response, it nevertheless seemed to have an effect on the immune system. For instance, Audencel led to a significant up-regulation of the Th1-related immunovariables ELISPOT IFNγ, the transcription factor T-bet in the blood and ELISPOT IL-2 in a dose-dependent manner upon vaccination. Post-vaccination levels of ELISPOT IFNγ and CD8+ cells in the blood were indicative of a significantly better survival. In summary, Audencel failed to reach an improvement of survival in the recent phase II clinical trial. No clinical efficacy was registered. Our concomitant immunological work presented here indicates that outcome under Audencel was influenced by the state of the immune system. On the other hand, Audencel also seemed to have stimulated the immune system. Overall, these immunological considerations suggest that DC immunotherapy against glioblastoma should be studied further – with the goal of translating an apparent immunological response into a clinical response. Future research should concentrate on investigating augmentation of immune reactions through combination therapies or on developing meaningful biomarkers.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0621-2) contains supplementary material, which is available to authorized users.

Audencel Immunotherapy Based on Dendritic Cells Has No Effect on Overall and Progression-Free Survival in Newly Diagnosed Glioblastoma: A Phase II Randomized Trial

“…The vaccination was well-tolerated, and no signs of autoimmunity were detected. Vaccinated patients developed tumor directed immune responses [ 42 ], so it seems justified to further develop vaccination strategies that take into account the failure of this trial in the future speculatively by combining DC vaccination with the administration of immune check point inhibitors, and by increasing the dose or other strategies.…”

“…The addition of Audencel, an autologous DC-based vaccine with tumor peptides, to SOC in patients with newly diagnosed GBM failed to prolong progression-free survival (PFS) and OS. However, vaccinated patients developed an active immune response, as shown by the associated in vitro surveillance [ 42 ], although this was not sufficient to avoid tumor recurrence. The median OS of 18.3 months compares to the actually reported treatment results for GBM patients [ 4 , 6 , 7 ].…”

Clinical implication of cellular vaccine in glioma: current advances and future prospects

“…In a prospective case control study that enrolled 47 GBM patients with DC vaccine adjuvant therapy, better outcomes were predicted with younger age and a lower programmed cell death protein 1 (PD-1) + /CD8 + ratio in TILs and PBMCs [ 90 ]. Further analysis of the immune system factors demonstrated that the patients with an immune system equipped with favorable pre-existing or post-vaccination anti-tumor capabilities, such as IFN γ secretion and CD8 + cells, are more likely to live longer [ 91 ]. Also, another clinical trial protocol of DC vaccination, including inclusion/exclusion criteria, was proposed and may increase the immune response and safety in pediatric and adult subjects [ 92 , 93 ].…”

Enhanced Human T Lymphocyte Antigen Priming by Cytokine-Matured Dendritic Cells Overexpressing Bcl-2 and IL-12

“…Dendritic cell (DC)-based vaccination can be used to induce host antitumor immunity and has shown promising clinical efficacy against some tumors (Yu et al, 2004;De Vleeschouwer et al, 2008;Cho et al, 2012;Mitchell et al, 2015;Erhart et al, 2018;Reap et al, 2018). Nevertheless, most clinical trials using DC vaccines, prepared with a variety of protocols, in cancer therapy show only limited efficacy, suggesting the need to optimize these clinical protocols (Vandenberk et al, 2015;Constantino et al, 2016).…”