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

Abstract

Dendritic cells (DCs) are antigen-presenting cells that are capable of priming anti-tumor immune responses, thus serving as attractive tools to generate tumor vaccines. In this multicentric randomized open-label phase II study, we investigated the efficacy of vaccination with tumor lysate-charged autologous DCs (Audencel) in newly diagnosed glioblastoma multiforme (GBM). Patients aged 18 to 70 years with histologically proven primary GBM and resection of at least 70% were randomized 1:1 to standard of care (SOC) or SOC plus vaccination (weekly intranodal application in weeks seven to 10, followed by monthly intervals). The primary endpoint was progression-free survival at 12 months. Secondary endpoints were overall survival, safety, and toxicity. Seventy-six adult patients were analyzed in this study. Vaccinations were given for seven (3–20) months on average. No severe toxicity was attributable to vaccination. Seven patients showed flu-like symptoms, and six patients developed local skin reactions. Progression-free survival at 12 months did not differ significantly between the control and vaccine groups (28.4% versus 24.5%, p = 0.9975). Median overall survival was similar with 18.3 months (vaccine: 564 days, 95% CI: 436–671 versus control: 568 days, 95% CI: 349–680; p = 0.89, harzard ratio (HR) 0.99). Hence, in this trial, the clinical outcomes of patients with primary GBM could not be improved by the addition of Audencel to SOC.

Fingolimod Augments Monomethylfumarate Killing of GBM Cells

“…However, the median survival for GBM patients has only marginally improved over the past two decades when these drugs have been available. Checkpoint inhibitory and cellular immunotherapies have yet to exhibit any significant alteration in progression free or overall survival (43,44). If we cannot enhance the immune system to attack GBM tumor cells, we reasoned, our initial conceptual approach became instead to attack the immune cell-rich soil in which the GBM tumor cells require to grow, thereby suppressing tumor cell growth and invasion, and with the hope that this will also enhance the lethality of standard of care therapeutics.…”

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

“…To prepare the intended immunological investigation of the Audencel clinical trial, we started with mapping the availability of patients and samples for research. While the concomitant clinical paper by Buchroithner et al [ 2 ] had to follow stringent regulatory criteria (e.g. age) for formal efficacy assessment and could analyse 34 vaccinated patients, for the experimental immunology research described here, it was possible to analyse 43 patients (with available samples) that were vaccinated in the course of the clinical trial.…”

“…A topic to consider here is the potential impact of Temozolomide chemotherapy. Buchroithner et al [ 2 ] speculate that it could have an influence on outcome. That theory is in line with our observations: indeed, there seems to be an association of anti-tumor immune capabilities and survival.…”

“…This maturation step as well as the fact that loading with autologous whole tumor lysate generates a personalized vaccine should in theory mean a technically advanced, promising concept [ 6 , 11 ]. But the trial based on the Audencel technique failed to show clinical efficacy (see Buchroithner et al [ 2 ]) when assessing progression-free and overall survival in all patients. One potential reason identified by Buchroithner et al for Audencel’s failure is the temporal proximity to the concomitant chemotherapy weakening the immune system.…”

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

“…Accounting for the narrow therapeutic index of rhIL-12 [ 84 ], the alteration of chemoresistance-associated peptides may achieve susceptibility of TAA-expressing glioma cells to the specific immune response in DC-based immunotherapy. However, vaccination with Audencel, a tumor lysate-charged autologous DC vaccine, failed to improve progression-free survival and median overall survival, although no severe toxicity was observed in those newly diagnosed with GBM ( N = 76) [ 85 ]. The factors dictating the efficacy of DC vaccines may represent a viable strategy to improve anti-tumor immunotherapy.…”