First results on survival from a large Phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma

Abstract

BackgroundStandard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma.MethodsAfter surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).ResultsFor the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone.ConclusionsAddition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival.Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1; initially registered 19 September 2002

A Novel Anti-PD-L1 Vaccine for Cancer Immunotherapy and Immunoprevention

“…Sipuleucel-T prolongs patient survival, but has little or no effect on clinical disease progression or biomarker kinetics. Liau LM et al recently reported that vaccinations with an autologous tumor lysate-pulsed dendritic cell (DCVax-L) after surgery and chemoradiotherapy likely extended survival in patients with newly diagnosed glioblastoma in a Phase Three trial [10]. Recently, we found that a genetically modified DC vaccine elicited potent tumor-associated antigen-specific T cell responses and yielded improved survival rate in acute leukemia patients [11].…”

Preservation of cell-based immunotherapies for clinical trials

“…The surveyed cryopreserved DC-based clinical trials were also primarily in phase 1 and 2 (except for DCVax-L [43] in phase 3 and DEN-STEM recruiting in phase 2/3), so the supply chain was shortened by inhouse manufacturing and on-site administration. As these DC vaccines progress into later phases of clinical investigation and multi-site studies, centralized manufacturing and distribution will become necessary.…”

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

“…Immune checkpoint inhibitors have demonstrated little efficacy as monotherapy in GBM, and studies of other immunotherapeutic approaches, including oncolytic viral therapy and dendritic cell vaccination, have generally failed to produce rates of response or stable disease above 20% [4,12,13,25,26]. Immunologically, GBM is characterized by a highly suppressive tumor microenvironment [12], and for most patients, there is scant intratumoral infiltration of effector T cells [27,28].…”