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

Anthony E Maida,Kevin Petrecca,Andrew Brenner ,Andrew E Sloan,Steven R Abram ,Scott Lindhorst,Richard M Green,Jose Lutzky,Jian Campian ,Christopher Duma,Timothy F Cloughesy,Paul J Mulholland ,Heinrich Elinzano,Kevin A Walter,Manfred Westphal,Robert Aiken,Simon Khagi,David Piccioni,Michael Schulder,Stacy D D’Andre,Charles S Cobbs,Jai Grewal,Pamela New ,Michael Salacz,Edward J Dropcho,Linda M Liau,Daniela Bota ,Tobias Walbert,Matthew G Ewend,Yaron A Moshel,Tom Mikkelsen,Robert M Prins,Keyoumars Ashkan,Rekha Chaudhary,David Tran ,Timothy Pluard ,Sarah Taylor,David S Baskin,William G Loudon,Jason Heth ,John L Villanó ,Gabriele Schackert,Fabio Iwamoto ,Victor Tse,John Trusheim ,Lynne Taylor ,Michel Lacroix,David Avigan ,Kevin O Lillehei,Steven Toms ,Michael Pearlman,Steven Brem,Marnix L Bosch,Samuel Goldlust ,Jana Portnow,Santosh Kesari,Dietmar Krex,Julian K Wu ,F Geoffroy ,Raphael P Davis,David Mathieu,Clement Pillainayagam ,Lyndon J Kim,Sven-Axel May,Karen Fink ,Hans-Jörg Meisel ,Paul Duic,Reid C Thompson,Arnold B Etame

doi:10.1186/s12967-018-1507-6

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

Highlights

Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide
We have previously demonstrated the effectiveness of Dendritic cells (DCs) vaccination in pre-clinical models [14,15,16], and early stage clinical trials have shown substantial promise [17,18,19]
We describe the blinded interim data of the overall ITT patient population enrolled in a Phase 3 randomized, double-blinded, placebo-controlled clinical trial of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) for newly diagnosed glioblastoma

Summary

Introduction

Standard 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. Median overall survival (mOS) under this SOC is only 15–17 months [2, 3], and ≤ 5% of patients are alive at 5 years [3]. For more than a decade, our group and others have been testing active vaccination strategies, such as DCs pulsed with tumor lysates or synthetic peptides to induce antitumor immunity in glioblastoma patients [12, 13]. We have previously demonstrated the effectiveness of DC vaccination in pre-clinical models [14,15,16], and early stage clinical trials have shown substantial promise [17,18,19]

Methods

Results

Discussion

Conclusion