Question  Is treatment with autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L) associated with improved overall survival (OS) for patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) compared with standard of care (SOC)?

Findings  In this phase 3 nonrandomized controlled trial of 331 patients, patients with nGBM receiving DCVax-L had a median OS of 19.3 months from randomization (22.4 months from surgery), while contemporaneous, matched external control patients treated with SOC had a median OS of 16.5 months from randomization; for patients with rGBM, median OS was 13.2 months from relapse in the DCVax-L group vs 7.8 months in the external control cohort. Meaningful increases in the long-term tails of the survival curves in both nGBM and rGBM were also observed.

Meaning  In this study, adding DCVax-L to SOC was associated with a clinically meaningful and statistically significant improvement in median OS for patients with both nGBM and rGBM compared with matched, contemporaneous external controls.

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 RegistrationClinicalTrials.gov Identifier: NCT00045968

Glioblastomas are aggressive, extremely heterogeneous, immunologically “cold,” and rapidly lethal. There is a pressing need for new treatments and for novel clinical trial designs to streamline their development.

This trial tested a novel fully personalized active immunotherapy. The trial also implemented an innovative design that could help accelerate advances in the field.

The survival benefit with DCVax-L vs ECP increased over time in the tails of the survival curves, with 13.0% vs 5.7% survival at 60 months in patients with nGBM and 11.1% vs 5.1% survival at 30 months after recurrence in patients with rGBM. Also of note, patients receiving DCVax-L have survived for years after completing their vaccine doses, which could be due to an effective memory immune response.³⁶

Although the absolute survival was greater in patients with positive prognostic factors, the relative survival benefit of DCVax-L vs ECPs was larger in certain patients who generally fare worse with SOC, including older patients, patients with substantial residual tumor, and patients with recurrent disease. These encouraging results suggest that cancer vaccines could be relevant for a broad range of clinical settings.

The mechanism of action of DC vaccines has been previously reported.^6,7 Using DCs as the active agent and antigen delivery method can mobilize a broader immune response (including diverse populations of T cells)³⁶ than with other agents. Second, using autologous rather than standardized antigens addresses the extreme heterogeneity of glioblastoma and can ensure that the treatment is targeting antigens actually present on the patient’s tumor. Third, distinctively, targeting the full repertoire of antigens by using tumor lysate can prevent the patient’s tumor from mutating around the targeted antigens, as has been seen when only one or a few antigens are targeted.^24,25

Although the primary end points of this study focused on OS, exploratory analyses of immunogenicity and biomarkers of immune activation and sensitization that may correlate with therapeutic benefit are planned. We have previously shown that CD8⁺ and CD4⁺ T cells can traffic into glioblastomas following DC vaccination, which correlates with survival,^37,38 and we plan to confirm these prior findings with this larger phase 3 data set. Similarly, analyses of patient characteristics and baseline immune parameters (eg, tumor immune activation signatures, tumor infiltrating lymphocytes) will be correlated with outcomes but are beyond the scope of this initial report.

Treatment with DCVax-L can potentially be combined with a wide range of other treatment agents (including checkpoint inhibitors, cytokines, targeted therapies, chemotherapies, or oncolytic virus therapies).³⁹ The robust survival benefit in patients with MGMT methylated tumors who received DCVax-L could reflect a cooperative effect between temozolomide⁴⁰ and DCVax-L, an increase in somatic mutations associated with MGMT methylation⁴¹ or temozolomide-induced hypermutation in MGMT methylated tumors.⁴²

The benign safety profile observed with DCVax-L can enable treatment of patients vulnerable to adverse events. Furthermore, it avoids the need (and cost) for other treatments to manage side effects.

This trial highlights the feasibility and appropriateness of using independently selected, contemporaneous, matched, and validated ECPs when a traditional RCT is not feasible.⁸ This approach is highly relevant for glioblastoma, where key prognostic factors are known, patient survival remains consistently dismal, and new approaches are sorely needed to streamline and accelerate clinical trials.

This study has limitations. Since individual patient-level data for the ECPs were not available for this trial, as is often the case, propensity score matching could not be performed, which is a potential limitation of this study. However, the MAIC analysis applied here is a powerful method to overcome the lack of such individual patient data and to enable matching of specific patient characteristics in external controls compared with patients in the investigational group. This method also has wider general applicability to provide reliable comparative evidence of benefit.¹⁸

This phase 3, nonrandomized, externally controlled trial found that the addition of DCVax-L to SOC was associated with a clinically meaningful and statistically significant extension of overall survival in both nGBM and rGBM. Treatment with DCVax-L also had an excellent safety profile and noteworthy tails of long-term survival curves.

Accepted for Publication: August 27, 2022.

Published Online: November 17, 2022. doi:10.1001/jamaoncol.2022.5370

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2022 Liau LM et al. JAMA Oncology.

Corresponding Author: Marnix L. Bosch, PhD, Northwest Biotherapeutics, Inc, 4800 Montgomery Ln, Bethesda, MD 20814 (marnix@nwbio.com).

Author Contributions: Dr Bosch had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Liau, Ashkan, Ansstas, Walter, Prins, Boynton, Bosch.

Acquisition, analysis, or interpretation of data: Liau, Ashkan, Brem, Campian, Trusheim, Iwamoto, Tran, Ansstas, Cobbs, Heth, Salacz, D'Andre, Aiken, Moshel, Nam, Pillainayagam, Wagner, Walter, Chaudhary, Goldlust, Lee, Bota, Elinzano, Grewal, Lillehei, Mikkelsen, Walbert, Abram, Brenner, Ewend, Khagi, Lovick, Portnow, Kim, Loudon, Martinez, Thompson, Avigan, Fink, Geoffroy, Giglio, Gligich, Krex, Lindhorst, Lutzky, Meisel, Nadji-Ohl, Sanchin, Sloan, Taylor, Wu, Dunbar, Etame, Kesari, Mathieu, Piccioni, Baskin, Lacroix, May, New, Pluard, Toms, Tse, Peak, Villano, Battiste, Mulholland, Pearlman, Petrecca, Schulder, Prins, Boynton, Bosch.

Drafting of the manuscript: Liau, Ashkan, Cobbs, Elinzano, Brenner, Kim, Nadji-Ohl, Peak, Mulholland, Pearlman, Prins, Boynton, Bosch.

Critical revision of the manuscript for important intellectual content: Liau, Ashkan, Brem, Campian, Trusheim, Iwamoto, Tran, Ansstas, Heth, Salacz, D'Andre, Aiken, Moshel, Nam, Pillainayagam, Wagner, Walter, Chaudhary, Goldlust, Lee, Bota, Grewal, Lillehei, Mikkelsen, Walbert, Abram, Ewend, Khagi, Lovick, Portnow, Loudon, Martinez, Thompson, Avigan, Fink, Geoffroy, Giglio, Gligich, Krex, Lindhorst, Lutzky, Meisel, Sanchin, Sloan, Taylor, Wu, Dunbar, Etame, Kesari, Mathieu, Piccioni, Baskin, Lacroix, May, New, Pluard, Toms, Tse, Villano, Battiste, Mulholland, Petrecca, Schulder, Prins, Boynton.

Statistical analysis: Liau, Bosch.

Administrative, technical, or material support: Liau, Ashkan, Brem, Iwamoto, Tran, Salacz, D'Andre, Aiken, Moshel, Nam, Wagner, Walter, Goldlust, Bota, Lillehei, Mikkelsen, Walbert, Abram, Brenner, Krex, Nadji-Ohl, Sloan, Wu, Dunbar, Baskin, Tse, Villano, Battiste, Pearlman, Petrecca, Boynton.

Supervision: Liau, Ashkan, Brem, Campian, Trusheim, Ansstas, Walter, Goldlust, Lovick, Loudon, Geoffroy, Kesari, Piccioni, Pluard, Toms, Peak, Prins, Bosch.

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.

Funding/Support: This study was supported by Northwest Biotherapeutics, Inc.

Role of the Funder/Sponsor: Northwest Biotherapeutics contributed to the design of the study together with the principal investigators and oversaw the conduct of the study by the independent contract research organizations, which were responsible for all collection and management of the data. Northwest Biotherapeutics participated in the preparation, review, and approval of the manuscript; and in the decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Information: The data from the trial were held and statistically analyzed by Quantics, which had no additional input into the manuscript or interpretation of the results. All data pertaining to this article were reviewed in full by Dr Bosch.

Question  Is treatment with autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L) associated with improved overall survival (OS) for patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) compared with standard of care (SOC)?

Findings  In this phase 3 nonrandomized controlled trial of 331 patients, patients with nGBM receiving DCVax-L had a median OS of 19.3 months from randomization (22.4 months from surgery), while contemporaneous, matched external control patients treated with SOC had a median OS of 16.5 months from randomization; for patients with rGBM, median OS was 13.2 months from relapse in the DCVax-L group vs 7.8 months in the external control cohort. Meaningful increases in the long-term tails of the survival curves in both nGBM and rGBM were also observed.

Meaning  In this study, adding DCVax-L to SOC was associated with a clinically meaningful and statistically significant improvement in median OS for patients with both nGBM and rGBM compared with matched, contemporaneous external controls.

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