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Autologous Tumor Lysate–Loaded Dendritic Cell Vaccination Extends Survival Among Patients With Newly Diagnosed and Recurrent Glioblastoma
TAKE-HOME MESSAGE
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This multicenter, international, phase III, nonrandomized, externally controlled trial evaluated the safety and efficacy of the addition of an autologous tumor lysate–loaded dendritic cell vaccine (DCVax-L) to standard-of-care (SOC) treatments in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM). Patients with nGBM who received the vaccine had a median overall survival (mOS) of 19.3 months versus 16.5 months from randomization in contemporaneous matched external controls. For patients with rGBM who received the vaccine, mOS was 13.2 months versus 7.8 months in the control group. The vaccine was relatively well-tolerated, with only 5 serious adverse events observed in 2151 doses (3 of these being cerebral edema, grade 2 or 3).
- The addition of DCVax-L to SOC resulted in a clinically meaningful and statistically significant survival benefit with an acceptable toxicity profile in both patients with nGBM and rGBM.
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
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.
Additional Info
Disclosure statements are available on the authors' profiles:
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
JAMA Oncol 2022 Nov 17;[EPub Ahead of Print], LM Liau, K Ashkan, S Brem, JL Campian, JE Trusheim, FM Iwamoto, DD Tran, G Ansstas, CS Cobbs, JA Heth, ME Salacz, S D'Andre, RD Aiken, YA Moshel, JY Nam, CP Pillainayagam, SA Wagner, KA Walter, R Chaudary, SA Goldlust, IY Lee, DA Bota, H Elinzano, J Grewal, K Lillehei, T Mikkelsen, T Walbert, S Abram, AJ Brenner, MG Ewend, S Khagi, DS Lovick, J Portnow, L Kim, WG Loudon, NL Martinez, RC Thompson, DE Avigan, KL Fink, FJ Geoffroy, P Giglio, O Gligich, D Krex, SM Lindhorst, J Lutzky, HJ Meisel, M Nadji-Ohl, L Sanchin, A Sloan, LP Taylor, JK Wu, EM Dunbar, AB Etame, S Kesari, D Mathieu, DE Piccioni, DS Baskin, M Lacroix, SA May, PZ New, TJ Pluard, SA Toms, V Tse, S Peak, JL Villano, JD Battiste, PJ Mulholland, ML Pearlman, K Petrecca, M Schulder, RM Prins, AL Boynton, ML BoschFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Glioblastomas are characterized by a paucity of infiltrating T cells and an immunosuppressive myeloid component. To date most immunotherapeutic strategies have been unsuccessful.
Liau et al recently reported the results of a phase III trial evaluating the addition of a dendritic cell vaccine, DCVax, to standard radiochemotherapy in patients with newly diagnosed glioblastomas. A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax group and 99 to the placebo group. The primary endpoint was progression-free survival (PFS) in the initial study and was not different between the groups. The median PFS was 6.2 (95%CI, 5.7–7.4) months for patients receiving DCVax and 7.6 (95% CI, 5.6–10.9) months for the placebo group (P = .47). Because a significant number of patients in the control group crossed over to receive the vaccine and the difficulties in determining PFS, the primary and secondary endpoints of the study were changed to overall survival (OS) in patients with newly diagnosed glioblastoma and those with recurrent glioblastoma GBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other randomized clinical trials.
The new analysis showed that the median OS (mOS) for the 232 patients with newly diagnosed glioblastoma receiving DCVax was 19.3 (95% CI, 17.5–21.3) months from randomization (22.4 months from surgery) compared with 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). For the 64 patients with recurrent glioblastoma receiving DCVax, mOS was 13.2 (95% CI, 9.7–16.8) months from relapse versus 7.8 (95% CI, 7.2–8.2) months among control patients (HR, 0.58; 98% CI, 0.00–0.76; P < .001).
Survival was improved in patients with newly diagnosed glioblastoma with methylated MGMT receiving DCVax compared with external control patients (HR, 0.74; 98% CI, 0.55–1.00; P = .03).
The authors conclude that the addition of DCVax to standard-of-care radiochemotherapy resulted in clinically meaningful and statistically significant extension of survival among patients with both newly diagnosed and recurrent glioblastoma. However, there are many significant concerns about the data that call into question the validity of the conclusions. A major concern is the lack of patient-level data in the external control group, reducing the utility of that control. There are also other sources of bias such as exclusion of patients with rapidly growing tumors from enrolling into the trial and the likely selection of good prognosis patients in the control group for administration of vaccine. As a result of these and other concerns, the therapeutic value of this vaccine remains unclear.