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Randomized Controlled Trial
. 2023 Jan 1;9(1):112-121.
doi: 10.1001/jamaoncol.2022.5370.

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial

Linda M Liau  1 , Keyoumars Ashkan  2 , Steven Brem  3 , Jian L Campian  4 , John E Trusheim  5 , Fabio M Iwamoto  6   7 , David D Tran  8 , George Ansstas  9 , Charles S Cobbs  10 , Jason A Heth  11 , Michael E Salacz  12 , Stacy D'Andre  13 , Robert D Aiken  14 , Yaron A Moshel  14 , Joo Y Nam  15 , Clement P Pillainayagam  16 , Stephanie A Wagner  17 , Kevin A Walter  18 , Rekha Chaudhary  19 , Samuel A Goldlust  20 , Ian Y Lee  21 , Daniela A Bota  22 , Heinrich Elinzano  23 , Jai Grewal  24 , Kevin Lillehei  25 , Tom Mikkelsen  21 , Tobias Walbert  21 , Steven Abram  26 , Andrew J Brenner  27 , Matthew G Ewend  28 , Simon Khagi  29 , Darren S Lovick  30 , Jana Portnow  31 , Lyndon Kim  32 , William G Loudon  33 , Nina L Martinez  34 , Reid C Thompson  35 , David E Avigan  36 , Karen L Fink  37 , Francois J Geoffroy  38 , Pierre Giglio  39 , Oleg Gligich  40 , Dietmar Krex  41 , Scott M Lindhorst  42 , Jose Lutzky  43 , Hans-Jörg Meisel  44 , Minou Nadji-Ohl  45 , Lhagva Sanchin  44 , Andrew Sloan  46 , Lynne P Taylor  47 , Julian K Wu  47 , Erin M Dunbar  48 , Arnold B Etame  49 , Santosh Kesari  50 , David Mathieu  51 , David E Piccioni  52 , David S Baskin  53 , Michel Lacroix  54 , Sven-Axel May  55 , Pamela Z New  56 , Timothy J Pluard  57 , Steven A Toms  58 , Victor Tse  59 , Scott Peak  59 , John L Villano  60 , James D Battiste  61 , Paul J Mulholland  62 , Michael L Pearlman  63 , Kevin Petrecca  64 , Michael Schulder  65 , Robert M Prins  66 , Alton L Boynton  67 , Marnix L Bosch  67
Affiliations
Randomized Controlled Trial

Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma: A Phase 3 Prospective Externally Controlled Cohort Trial

Linda M Liau et al. JAMA Oncol. .

Abstract

Importance: Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.

Objective: To investigate whether adding autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.

Design, setting, and participants: This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.

Interventions: The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.

Main outcomes and measures: The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.

Results: A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03).

Conclusions and relevance: In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.

Trial registration: ClinicalTrials.gov Identifier: NCT00045968.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Liau reported serving on the board of directors of ClearPoint Neuro outside the submitted work and having a patent pending for combinations of inhibitors with dendric cell vaccines to treat cancer. Dr Ashkan reported receiving grants from Northwest Biotherapeutics during the conduct of the study. Dr Brem reported receiving travel support from Northwest Biotherapeutics outside the submitted work. Dr Campian reported receiving grants from NeoImmue Tech and support for investigator-initiated clinical trials from Incyte, Merck, and Ipsen outside the submitted work. Dr Iwamoto reported receiving grants from Northwest Biotherapeutics and serving on the steering committee of this trial during the conduct of the study and receiving personal fees from AbbVie, Alexion, Gennao Bio, Novocure, Kiyatec, Medtronic, Merck, Guidepoint, Mimivax, Massive Bio, Tocagen, Regeneron, and Xcures outside the submitted work. Dr Tran reported receiving grants from Novocure, Moteris, Lacerta, Sarepta, Merck, Novartis, Northwest Biotherapeutics, Stemline, Celldex, Orbus, TVax, and Tocagen; receiving travel support from Novartis; and serving on the advisory board of Novocure during the conduct of the study. Dr Goldlust reported receiving institutional support from Northwest Biotherapeutics during the conduct of the study; receiving consulting fees from Boston Biomedical, Sumitomo Danippon Pharma, Cornerstone Specialty Network, Cellevolve, Daiichi Sankyo, and Novocure; serving on the speakers’ bureau for Novocure and Physicians Education Resources; receiving food and drink from Novocure; and owning stock in COTA outside the submitted work. Dr Grewal reported receiving personal fees from AstraZeneca, Vivacitas Oncology, and xCures; receiving sample medication from AbbVie/Allergan; and being the founder of Genomet outside the submitted work. Dr Avigan reported serving on the advisory boards of Bristol Myer Squibb, Chugai, Merck, Kite, and Legend; receiving grants from Sanofi, and serving as a consultant for Parexel outside the submitted work. Dr Fink reported receiving funding from Northwest Biotherapeutics during the conduct of the study and receiving funding from Novocure, Denovo Biopharma, Stemline, CNS Pharmaceuticals, Servier Pharmaceuticals/Agios, and Sumitoma Pharma outside the submitted work. Dr Giglio reported receiving study support from the Medical University of South Carolina during the conduct of the study; receiving grants from Denovo Biopharma, Novocure, BioMimetix, Celgene, EORTC, the Canadian Cancer Trials Group, Institut de Recherches Internationales Servier, the Global Coalition for Adapative Research, and Prelude outside the submitted work; and having a patent pending for the epitranscriptomic analysis of glioma. Dr Lutzky reported receiving grants from Bristol Myer Squibb and serving on the advisory boards of Iovance and Castle outside the submitted work. Dr Meisel reported receiving personal fees from BG Klinikum Bergmannstrost during the conduct of the study and receiving consulting fees paid to Regenerate Life Sciences from Stayble Therapeutics and royalties from Fehling Instruments outside the submitted work. Dr Sanchin reported receiving personal fees from BG Klinikum Bergmannstrost during the conduct of the study. Dr Dunbar reported receiving speaking fees from GT Medical during the conduct of the study. Dr Pluward reported receiving grants from Northwest Biotherapeutics during the conduct of the study. Dr Mulholland reported receiving support to attend a conference from Northwest Biotherapeutics during the conduct of the study. Dr Pearlman reported receiving compensation for serving as a site principal investigator from Northwest Biotherapeutics during the conduct of the study. Dr Prins reported having patent UCLA Case No. 2015-341 pending. Drs Boynton and Bosch reported being employees of and owning shares in Northwest Biotherapeutics, Inc. Dr Boynton reported having a patent held by Northwest Biotherapeutics. Dr Bosch reporting having patent 13/492693 pending.

Figures

Figure 1.
Figure 1.. Study Design and Flow
A, After the surgery and centralized histological confirmation of glioblastoma, patients underwent leukapheresis to obtain their immune cells and then received 6 weeks of standard of care (SOC) radiochemotherapy, following the Stupp protocol. The autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L) products and placebo (peripheral blood mononuclear cells) were both manufactured for all prospective patients during the 6 weeks of radiochemotherapy, prior to enrollment. The manufacturing process for DCVax-L is described in Liau et al. At the end of radiochemotherapy, patients who met the eligibility criteria were enrolled. B, Enrollment of patients into the study. a(Re)started day 0, 10, and 20 and beyond DCVax-L vaccination regimen at recurrence.
Figure 2.
Figure 2.. Overall Survival and Subgroup Analyses for Patients with Newly Diagnosed Glioblastoma
A, Kaplan-Meier plot comparing overall survival for patients with newly diagnosed glioblastoma treated with autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L) and 1366 contemporaneous matched external control participants (ECPs) treated with standard of care, derived from 5 other contemporaneous matched randomized clinical trials. B, Cox hazard ratios of overall survival in prespecified subgroups of participants receiving DCVax-L or treated with standard of care in external trials. In the age subgroup, there were 50 participants in the DCVax-L group and 45 in the ECP group aged 65 years or greater and 182 and 184, respectively in the younger than 65 years group; in the residual disease subgroup, there were 86 patients in the DCVax-L group and 163 in the ECP group with significant residual disease and 146 and 210, respectively, with minimal residual disease; in the MGMT (O6-methylguanine-DNA methyltransferase) subgroup, there were 90 patients in the DCVax-L group and 199 in the ECP group with methylated MGMT and 131 and 349, respectively, with unmethylated MGMT. Subgroup analyses of survival, using the same parameters as the comparator publications, are presented with 95% confidence intervals to facilitate comparisons with the ECP.
Figure 3.
Figure 3.. Overall Survival for Patients With Recurrent Glioblastoma
Kaplan-Meier plot comparing overall survival for patients with recurrent glioblastoma treated with autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L; ie, patients who were randomized to the placebo group and who crossed over to begin DCVax-L following recurrence) and 640 contemporaneous, matched external controls derived from 10 other contemporaneous randomized clinical trials.
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Comment in

References

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