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3 days to 20 Nov
NWBO: Once In A Decade Best Stock Investment -- Regulatory Approvals Coming! [Dec10, 2022 在第一页加了中文简述]
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When the US biotech media is run by mafia, mainstream UK media seems not:
Trial results suggest people with newly diagnosed glioblastoma could potentially be given extra years of life
www.theguardian.com
Glioblastoma is the commonest form of brain cancer and also one of the most aggressive, with people on average living 12-18 months after diagnosis. Photograph: Dr P Marazzi/Science Photo Library/Getty Images/Science Photo Library RF
Denis Campbell Health policy editor
Thu 17 Nov 2022 15.00 GMTLast modified on Thu 17 Nov 2022 15.48 GMT
The world’s first vaccine to treat deadly cancerous brain tumours can potentially give patients years of extra life, a global clinical trial has concluded.
A senior NHS doctor who was one of the trial’s chief investigators said the evidence showed DCVax had resulted in “astonishing” enhanced survival for patients.
The breakthrough could benefit the 2,500 people a year in the UK who are diagnosed with glioblastoma , the commonest form of brain cancer and also one of the most aggressive. People with the disease live on average just 12-18 months after diagnosis, some for even less.
One patient in the 331-person multicentre global study lived for more than eight years after receiving DCVax. In Britain, 53-year-old Nigel French is still alive seven years after having it.
“The total results are astonishing,” said Prof Keyoumars Ashkan, a neurosurgeon at King’s College hospital in London who was the European chief investigator of the trial. “The final results of this phase three trial … offer fresh hope to patients battling with glioblastoma.
The vaccine “was shown to prolong life and interestingly so in patients traditionally considered to have poorer prognosis”, such as older people and people for whom surgery was not an option, he added.
If approved by medical regulators, DCVax would be the first new treatment in 17 years for newly diagnosed glioblastoma patients and the first in 27 years for people in whom it had returned.
Trial researchers found that newly diagnosed patients who had the vaccine survived for 19.3 months on average, compared with 16.5 months for those who received a placebo.
Participants with recurrent glioblastoma who had had DCVax lived on average for 13.2 months after receiving it, compared with just 7.8 months for those who did not.
Overall 13% of people who received it lived for at least five years after diagnosis, while just 5.7% of those in the control group did so, according to the results of the trial, which were published on Thursday in the Journal of the American Medical Association Oncology.
The vaccine is a form of immunotherapy, in which the body’s immune system is programmed to track down and attack the tumour. It is the first developed to tackle brain tumours.
“The vaccine works by stimulating the patient’s own immune system to fight against the patient’s tumour. It provides a personalised solution, working with a patient’s immune system, which is the most intelligent system known to man,” said Ashkan.
“The vaccine is produced by combining proteins from a patient’s own tumour with their white blood cells. This educates the white cells to recognise the tumour.
“When the vaccine is administered, these educated white blood cells then help the rest of the patient’s immune system recognise the tumour as something it needs to fight against and destroy. Almost like training a sniffer dog.”
The vaccine is not yet available on the NHS. But Northwest Biotherapeutics, the US company that makes it, plans to seek regulatory approval so it can become available.
The charity Brain Tumour Research said “patients who have been starved of new clinical options for too long” needed to be able to access the treatment to prolong their lives.
“DCVax represents the first emerging therapy proven effective in treating glioblastoma since temozolomide chemotherapy in 2005 and what the brain tumour community hopes is for it to become affordable, possibly becoming standard of care – so available on the NHS,” said Dr Karen Noble, the charity’s director of research, policy and innovation.
“The average survival time for glioblastoma is devastatingly short – just 12 to 18 months. Stories like Mr French’s are rare but incredibly welcome. We are very encouraged by the final results of this trial,” she added.
Twenty of the 331 patients in the eight-year trial were in the UK, either at King’s or at University College London hospital. Overall 232 participants had DCVax and 99 a placebo. All 331 had surgery followed by radiotherapy and chemotherapy to remove as much of their tumour as possible, which is the standard treatment for glioblastoma.
Dr Henry Stennett, research information manager at Cancer Research UK, said, “What’s particularly exciting is that [the vaccine] can improve outcomes for people who don’t usually respond well to therapy. While it still needs to pass stringent regulatory approval, it could be a big step forwards in beating this type of brain tumour.”
Vaccine shown to prolong life of patients with aggressive brain cancer
Trial results suggest people with newly diagnosed glioblastoma could potentially be given extra years of life
patients with aggressive brain cancer
Trial results suggest people with newly diagnosed glioblastoma could potentially be given extra years of life
Glioblastoma is the commonest form of brain cancer and also one of the most aggressive, with people on average living 12-18 months after diagnosis. Photograph: Dr P Marazzi/Science Photo Library/Getty Images/Science Photo Library RF
Denis Campbell Health policy editor
Thu 17 Nov 2022 15.00 GMTLast modified on Thu 17 Nov 2022 15.48 GMT
The world’s first vaccine to treat deadly cancerous brain tumours can potentially give patients years of extra life, a global clinical trial has concluded.
A senior NHS doctor who was one of the trial’s chief investigators said the evidence showed DCVax had resulted in “astonishing” enhanced survival for patients.
The breakthrough could benefit the 2,500 people a year in the UK who are diagnosed with glioblastoma , the commonest form of brain cancer and also one of the most aggressive. People with the disease live on average just 12-18 months after diagnosis, some for even less.
One patient in the 331-person multicentre global study lived for more than eight years after receiving DCVax. In Britain, 53-year-old Nigel French is still alive seven years after having it.
“The total results are astonishing,” said Prof Keyoumars Ashkan, a neurosurgeon at King’s College hospital in London who was the European chief investigator of the trial. “The final results of this phase three trial … offer fresh hope to patients battling with glioblastoma.
The vaccine “was shown to prolong life and interestingly so in patients traditionally considered to have poorer prognosis”, such as older people and people for whom surgery was not an option, he added.
If approved by medical regulators, DCVax would be the first new treatment in 17 years for newly diagnosed glioblastoma patients and the first in 27 years for people in whom it had returned.
Trial researchers found that newly diagnosed patients who had the vaccine survived for 19.3 months on average, compared with 16.5 months for those who received a placebo.
Participants with recurrent glioblastoma who had had DCVax lived on average for 13.2 months after receiving it, compared with just 7.8 months for those who did not.
Overall 13% of people who received it lived for at least five years after diagnosis, while just 5.7% of those in the control group did so, according to the results of the trial, which were published on Thursday in the Journal of the American Medical Association Oncology.
The vaccine is a form of immunotherapy, in which the body’s immune system is programmed to track down and attack the tumour. It is the first developed to tackle brain tumours.
“The vaccine works by stimulating the patient’s own immune system to fight against the patient’s tumour. It provides a personalised solution, working with a patient’s immune system, which is the most intelligent system known to man,” said Ashkan.
“The vaccine is produced by combining proteins from a patient’s own tumour with their white blood cells. This educates the white cells to recognise the tumour.
“When the vaccine is administered, these educated white blood cells then help the rest of the patient’s immune system recognise the tumour as something it needs to fight against and destroy. Almost like training a sniffer dog.”
The vaccine is not yet available on the NHS. But Northwest Biotherapeutics, the US company that makes it, plans to seek regulatory approval so it can become available.
The charity Brain Tumour Research said “patients who have been starved of new clinical options for too long” needed to be able to access the treatment to prolong their lives.
“DCVax represents the first emerging therapy proven effective in treating glioblastoma since temozolomide chemotherapy in 2005 and what the brain tumour community hopes is for it to become affordable, possibly becoming standard of care – so available on the NHS,” said Dr Karen Noble, the charity’s director of research, policy and innovation.
“The average survival time for glioblastoma is devastatingly short – just 12 to 18 months. Stories like Mr French’s are rare but incredibly welcome. We are very encouraged by the final results of this trial,” she added.
Twenty of the 331 patients in the eight-year trial were in the UK, either at King’s or at University College London hospital. Overall 232 participants had DCVax and 99 a placebo. All 331 had surgery followed by radiotherapy and chemotherapy to remove as much of their tumour as possible, which is the standard treatment for glioblastoma.
Dr Henry Stennett, research information manager at Cancer Research UK, said, “What’s particularly exciting is that [the vaccine] can improve outcomes for people who don’t usually respond well to therapy. While it still needs to pass stringent regulatory approval, it could be a big step forwards in beating this type of brain tumour.”
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Yes here you go. It's official. the peer-reviewed journal paper is out:
Association of DCVax-L With Extension of Survival Among Patients With Glioblastoma
Association of DCVax-L With Extension of Survival Among Patients With Glioblastoma
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Took 50k profit off the table. When US main news media report it in the next few days (next week maybe), intended to take 100k more profit off the table. Will still keep the vast majority of shares until after regulatory approvals.
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Original Investigation
November 17, 2022
Linda M. Liau, MD, PhD1; Keyoumars Ashkan, MD, FRCP, FRCS2; Steven Brem, MD3; et al Jian L. Campian, MD, PhD4; John E. Trusheim, MD5; Fabio M. Iwamoto, MD6,7; David D. Tran, MD, PhD8; George Ansstas, MD9; Charles S. Cobbs, MD10; Jason A. Heth, MD11; Michael E. Salacz, MD12; Stacy D’Andre, MD13; Robert D. Aiken, MD14; Yaron A. Moshel, MD, PhD14; Joo Y. Nam, MD15; Clement P. Pillainayagam, MD16; Stephanie A. Wagner, MD17; Kevin A. Walter, MD18; Rekha Chaudary, MD19; Samuel A. Goldlust, MD20; Ian Y. Lee, MD21; Daniela A. Bota, MD, PhD22; Heinrich Elinzano, MD23; Jai Grewal, MD24; Kevin Lillehei, MD25; Tom Mikkelsen, MD, FRCPC21; Tobias Walbert, MD21; Steven Abram, MD26; Andrew J. Brenner, MD, PhD27; Matthew G. Ewend, MD28; Simon Khagi, MD29; Darren S. Lovick, MD30; Jana Portnow, MD31; Lyndon Kim, MD32; William G. Loudon, MD33; Nina L. Martinez, MD34; Reid C. Thompson, MD35; David E. Avigan, MD36; Karen L. Fink, MD, PhD37; Francois J. Geoffroy, MD38; Pierre Giglio, MD39; Oleg Gligich, MD40; Dietmar Krex, MD41; Scott M. Lindhorst, MD42; Jose Lutzky, MD43; Hans-Jörg Meisel, MD, PhD44; Minou Nadji-Ohl, MD45; Lhagva Sanchin, MD44; Andrew Sloan, MD46; Lynne P. Taylor, MD47; Julian K. Wu, MD47; Erin M. Dunbar, MD48; Arnold B. Etame, MD, PhD49; Santosh Kesari, MD, PhD50; David Mathieu, MD51; David E. Piccioni, MD, PhD52; David S. Baskin, MD53; Michel Lacroix, MD54; Sven-Axel May, MD55; Pamela Z. New, MD56; Timothy J. Pluard, MD57; Steven A. Toms, MD58; Victor Tse, MD59; Scott Peak, MD59; John L. Villano, MD, PhD60; James D. Battiste, MD, PhD61; Paul J. Mulholland, MD62; Michael L. Pearlman, MD63; Kevin Petrecca, MD, PhD64; Michael Schulder, MD65; Robert M. Prins, PhD66; Alton L. Boynton, PhD67; Marnix L. Bosch, PhD67
Author Affiliations Article Information
JAMA Oncol. Published online November 17, 2022. doi:10.1001/jamaoncol.2022.5370
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Association of DCVax-L With Extension of Survival Among Patients With Glioblastoma
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Key Points
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.
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
Introduction
Glioblastoma is a highly lethal brain cancer, with a nearly 100% recurrence rate and dismal patient survival. Standard of care (SOC) for newly diagnosed glioblastoma (nGBM) includes surgery, radiotherapy, and chemotherapy. Following initial surgery, tumors typically recur in 6 to 8 months,1 median overall survival (mOS) is 15 to 17 months, and 5-year survival is generally less than 5%.2 For recurrent glioblastoma (rGBM), there is no established SOC.3 Among more than 400 clinical trials since 2005, with more than 32 000 patients, testing diverse treatment modalities,4 only 1 phase 3 trial in nGBM and no phase 3 trials in rGBM have demonstrated a survival benefit.5
We report the overall survival (OS) and safety outcomes of a phase 3 nonrandomized controlled trial testing an autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) combined with SOC for treatment of glioblastoma. Dendritic cells present tumor antigens to the immune system, prime T cells, and mobilize antitumor responses.6,7
Many trials, especially for incurable diseases, incorporate a crossover design for feasibility and/or ethical reasons. A crossover was considered necessary when our study began in 2007 to make patient enrollment and retention feasible when novel immunotherapies were not yet generally viewed as promising for cancer. The crossover was also important to justify the placebo group for patients undergoing a leukapheresis—an invasive procedure necessary for blinding and for manufacturing vaccine but offering no benefit to patients in the placebo group if they could not receive their autologous vaccine.
The crossover design necessitated the use of external controls to evaluate OS. Traditional (ie, within-study) randomized control comparisons were infeasible, since most placebo group patients received DCVax-L through the crossover. When randomized clinical trials (RCTs) are not feasible, use of external controls is increasingly recognized as an effective way to enable comparative analyses of outcomes.8 There is also growing support for streamlining trials in the neuro-oncology field.9,10
Methods
Study Design and Oversight
This was originally a phase 3 randomized, double-blind clinical trial, with a crossover design. The trial was conducted at 94 sites in 4 countries (US, Canada, UK, and Germany). The screening and enrollment process and treatment assignment are described in Figure 1A and B.11,12 The trial protocol appears in Supplement 1.
The primary end point was OS in patients with nGBM from the time of randomization (a median of 3.1 months after surgery), and the secondary end point was OS in rGBM from the time of recurrence. Each group was compared with independently selected, contemporaneous, matched external control patients as prespecified in the Statistical Analysis Plan (SAP) (Supplement 1).
The original primary end point in the 2007 study protocol was progression-free survival (PFS) determined by magnetic resonance imaging (MRI). However, while the trial was underway, the difficulty of distinguishing actual disease progression from pseudo-progression comprised of inflammation or necrosis or from vaccine-induced infiltration of immune cells was recognized.13 Accordingly, the SAP for this study focused on OS.
On enrollment, patients were randomized 2:1 to either DCVax-L or placebo, plus SOC. Randomization was performed centrally by independent contract research organizations (CROs [Synteract, Parexel]).
Following tumor recurrence, all patients were allowed to cross over to start or continue receiving DCVax-L. The trial did not prescribe additional surgery at recurrence; the DCVax-L administered to crossover patients after recurrence was the product from the original surgery. All parties remained blinded to the treatment before crossover. Due to the crossover, the placebo group was depleted, and OS was assessed by comparison to external control populations (ECPs).
The protocol was approved by the relevant institutional review boards or ethics committees. The trial was performed in accordance with the Declaration of Helsinki.14 The data were collected and held by independent CROs (Synteract, Parexel) and were analyzed by independent statisticians (Quantics). Patients gave informed consent for tumor collection in presurgery screening and thereafter gave consent for study participation (Figure 1A).
Patients and Study Procedures
Patients aged 18 to 70 years with nGBM (World Health Organization grade 4), Karnofsky Performance Score (KPS) of 70 or greater, life expectancy of 8 or more weeks, and adequate laboratory values were eligible for enrollment (Figure 1A). Patients centrally determined (ICON) to have radiographic evidence of early disease progression15 following radiochemotherapy were excluded.
After initial diagnosis, all patients underwent surgery and collection of tumor tissue for manufacturing of DCVax-L. After surgery, diagnosis of glioblastoma was histologically confirmed centrally (Quest Diagnostics; Mayo Clinic). The MGMT (O6-methylguanine-DNA methyltransferase) gene promoter methylation status, IDH (isocitrate dehydrogenase) R132 mutation status, and postsurgery minimal (<2 cm2) vs significant (≥2 cm2) residual tumor were determined centrally (LabCorp; Mayo; ICON). The KPS was determined by the treating physician.
Patients underwent MRI before enrollment and every 2 months thereafter. Progression was assessed centrally (ICON) on a blinded basis. Adverse events were assessed throughout the study according to National Cancer Institute Common Terminology Criteria version 3.0.17
Patients received either DCVax-L or placebo on days 0, 10, and 20, then in months 2, 4, and 8 and months 12, 18, 24, and 30, with monthly temozolomide as SOC. Each DCVax-L dose comprised 2.5 million DCs injected intradermally in the upper arm, alternating arms between treatment visits. The placebo was unmanipulated peripheral blood mononuclear cells.
External Control Populations
The ECPs were determined by an independent expert firm (York Health Economics Consortium) and comprised patients from the control groups from contemporaneous RCTs closely matched to the current study based on 14 criteria prespecified in the SAP (Supplement 1). These studies met the “fit for purpose” criteria outlined by Mishra-Kalyani et al.8 We compared the treatment groups of the external trials to the ECPs to validate the methodology, applied sensitivity analyses to check for biases, and conducted a matching-adjusted indirect comparison (MAIC)18 to adjust for imbalances in individual patient characteristics (eAppendix 1 in Supplement 2).
Statistical Analysis
Primary End Point: OS in Patients With nGBM
All statistical analyses were conducted in SAS version 9.4 (SAS Institute). The primary end point was OS from randomization to death from any cause in patients with nGBM. The 1-sided significance level was 2.5%. The O’Brien-Fleming group sequential boundary function19 and alpha-spending function of Lan and DeMets20 were used to adjust for sequential testing of OS. The final analysis was conducted at the 1-sided 2.409% level. OS was analyzed using log-rank test at the appropriate α level. The hazard ratio (HR) and confidence intervals were calculated using the proportional hazards model with treatment as covariate. Individual control patient survival data were reconstructed by digitizing the published Kaplan-Meier (KM) curves.16 The algorithm to extract individual patient level data from published KM curves uses as inputs the x- and y-coordinates from digitized KM curves, the reported numbers at risk at various time points (which accounts for censored participants), and the total number of events reported. It then applies an iterative process to reconstruct the KM parameters, from which the individual patient data are obtained. Full details on the method are found in Guyot et al.16
Secondary End Point: OS in Patients With rGBM
For the secondary end point, OS in patients with rGBM was measured from first recurrence to death from any cause. The 1-sided significance level allocated to this end point was 2.5%. OS was analyzed using the log-rank test, and the HR and 95% CIs were calculated as described previously.
Landmark Analyses and KM Survival Curve Tails
The KM estimates of landmark survival rates at 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months were calculated along with Hall-Wellner 2-sided 95% CIs21 (adjusted for multiplicity). The numbers of patients available for comparison at late time points was small, especially in the control population, resulting in relatively wide confidence intervals.
Results
Patients and Treatments
From August 2007 to November 2015, 331 patients with nGBM were enrolled (Figure 1B). The median (range) age was 56 (19-73) years, 202 participants (61.0%) were men; 7 (2.1%), Black or African American; 16 (4.8%), Hispanic or Latino; and 294 (88.8%), White. Screening and enrollment were suspended from 2008 through 2011 due to the financial crisis, resumed on a limited basis in 2012, and 303 of the 331 patients (91.5%) were enrolled during 2012 to 2015.
All patients underwent surgical resection, recovery, leukapheresis, and 6 weeks of postoperative SOC radiochemotherapy prior to enrollment (Figure 1A). The median time from surgery to randomization was 3.1 months.
Of the 331 patients, 232 were randomized to initial DCVax-L treatment and 99 to placebo. Following tumor recurrence, 64 of the 99 patients in the placebo group crossed over to receive DCVax-L, while 120 of the 232 patients who had already received DCVax-L continued to receive DCVax-L. The patients, investigators, study team, and sponsor remained blinded to the treatments before crossover.
External Controls
The ECP for the primary end point (OS in nGBM) comprised 1366 patients with nGBM treated with SOC in the control groups of 5 comparator RCTs5,22-25 (eTable 1 in Supplement 2). The ECP for the secondary end point (OS in rGBM) comprised 640 patients with rGBM at first recurrence treated with either SOC therapies (lomustine, bevacizumab, or best supportive care) or a placebo in the control groups of 10 comparator RCTs26-35 (eTable 1 in Supplement 2).
The patient demographic characteristics and prognostic factors of the DCVax-L cohorts were well matched with the ECPs for both the primary and secondary end points, based on the 14 criteria prespecified in the SAP (Table 1; eAppendix and eTable 2 in Supplement 2). The analysis of each of the 15 comparator trials, substituting our ECP for the original control groups, confirmed that the outcomes were the same as originally reported (primary end point met or not met).
In the 5 sensitivity analyses conducted to address potential known and unknown confounders in the nGBM ECP, the HR results (range, 0.77-0.82) were comparable with the HR in all 5 studies included (HR, 0.80). In the sixth sensitivity analysis, dropping 2 of the 5 comparator studies22,23 because it was not clear whether they had excluded patients with early progression, the HR remained the same (0.80 in both). The MAIC analyses adjusted for imbalances in individual patient characteristics between the patients receiving DCVax-L and the nGBM ECPs by applying a weight to each patient in the DCVax-L cohort to result in a match with the patient characteristics of the external populations.
Survival Outcomes
OS in Patients With nGBM
The mOS for patients with nGBM assigned to the DCVax-L cohort at enrollment was 19.3 (95% CI, 17.5-21.3) months from the time of randomization (22.4 months from surgery) compared with 16.5 (95% CI, 16.0-17.5) months from randomization for the 1366-patient ECP (log-rank HR, 0.80; 95% CI, 0.00-0.94; P = .002) (Figure 2A). The data indicate a 20% relative reduction in risk of death at any point in time for patients with nGBM receiving DCVax-L, and this relative survival benefit increased over time (Table 2): 15.7% of patients receiving DCVax-L vs 9.9% of ECP patients were alive at 48 months after randomization, and 13.0% of DCVax-L patients vs 5.7% of ECP patients were alive at 60 months after randomization. The long-term survivors tended to have favorable prognostic characteristics, but these factors did not fully explain the survival observed (eFigure 2 in Supplement 2). The outcome of the MAIC analyses showed that after adjustment for imbalances in individual patient characteristics the difference in OS between the DCVax-L cohort and the ECP was still significant.
Six prespecified subgroup analyses were conducted (Figure 2B and eFigure 1 in Supplement 2). Patients receiving DCVax-L had HRs less than 1 in all subgroups, and the difference was statistically significant for 4 of the 6 subgroups at the 95% confidence level, and for 3 of the 6 subgroups when multiplicity correction was applied. In patients with nGBM with methylated MGMT, mOS was 30.2 (95% CI, 23.7-33.9) months from randomization (33.0 months from surgery) in 90 patients receiving DCVax-L vs 21.3 (95% CI, 18.3-25.1) months in the 199 patients in the ECP (HR, 0.74; 95% CI, 0.55-1.00, P = .03).
OS in Patients With rGBM
The 64 patients with rGBM who received DCVax-L after recurrence had mOS of 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months in the ECP (HR, 0.58; 0.00-0.76; P < .001) (Figure 3). These data indicate a 42% relative reduction in risk of death at any point in time for patients with rGBM treated with DCVax-L at first recurrence, and this survival benefit continued over time (Table 2): 20.7% of the patients receiving DCVax-L vs 9.6% of the patients in the ECP were alive at 24 months after recurrence, and 11.1% vs 5.1% were alive at 30 months after recurrence.
Postprogression Treatments
The trial design did not prescribe a second surgery on recurrence, and most patients did not have a second surgery. Only 18 of the 64 patients in the placebo group (28.1%) who crossed over to start receiving DCVax-L after progression as patients with rGBM had any surgery beyond the original tumor resection when newly diagnosed. The patients who had additional surgery had shorter survival than patients who had no additional surgery (postprogression mOS of 11.8 [95% CI, 8.5-14.7] months vs 13.4 [95% CI, 7.7-19.3] months). For all crossover patients, the DCVax-L vaccines administered after progression were the products made after the original surgery. No new DCVax-L vaccines were made following any postprogression surgery.
The trial design allowed additional treatments during the postrecurrence crossover period. Among the 232 patients in the DCVax-L group, 22 received bevacizumab and lomustine (9.5%), 65 (28.0%) received only bevacizumab, and 15 (6.5%) received only lomustine. Participants who received bevacizumab had shorter survival times than those who did not (16.4 [95% CI, 14.2-18.6] vs 22.1 [95% CI, 19.4-24.9] months). There was no significant survival difference between participants who received lomustine vs those who did not (18.6 [95% CI, 13.6-23.6] vs 19.3 [95% CI, 16.8-21.7] months).
Eight of the 232 patients (3.4%) receiving DCVax-L were treated with tumor-treating fields (TTF) following recurrence. Four of those 8 patients (50.0%) continued receiving DCVax-L while using the TTF device after recurrence and survived from 22.6 to more than 72.7 months from randomization. Four of the 8 patients (50.0%) stopped receiving DCVax-L while using the TTF device post-recurrence, and survived from 8.9 to 29.2 months from randomization.
Progression-Free Survival
The PFS end point became infeasible for this trial due to the challenges now well recognized in trying to distinguish true progression from pseudo-progression (including vaccine-induced immune cell infiltration).13 There were 494 imaging time points when possible progression was observed by the independent radiologists, and 256 of these (>50%) required adjudication due to discordant interpretations. Based on these assessments, the median PFS was 6.2 (95% CI, 5.7-7.4) months for patients receiving DCVax-L and 7.6 (95% CI, 5.6-10.9) months for the placebo group. This difference was not statistically significant (P = .47).
Safety and Toxic Effects
The DCVax-L was well tolerated. Of 2151 total doses of DCVax-L administered, only 5 serious adverse events were deemed at least possibly related to the investigational treatment. There were 3 cases of intracranial edema (2 at grade 3; 1 at grade 2), 1 case of nausea (grade 3), and 1 case of lymph node infection (grade 3). There was no evidence of any auto-immune reactions or cytokine storm among patients who received DCVax-L.
Discussion
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.
Limitations
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
Conclusions
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.
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Article Information
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.
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November 17, 2022
Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination With Extension of Survival Among Patients With Newly Diagnosed and Recurrent GlioblastomaA Phase 3 Prospective Externally Controlled Cohort Trial
Linda M. Liau, MD, PhD1; Keyoumars Ashkan, MD, FRCP, FRCS2; Steven Brem, MD3; et al Jian L. Campian, MD, PhD4; John E. Trusheim, MD5; Fabio M. Iwamoto, MD6,7; David D. Tran, MD, PhD8; George Ansstas, MD9; Charles S. Cobbs, MD10; Jason A. Heth, MD11; Michael E. Salacz, MD12; Stacy D’Andre, MD13; Robert D. Aiken, MD14; Yaron A. Moshel, MD, PhD14; Joo Y. Nam, MD15; Clement P. Pillainayagam, MD16; Stephanie A. Wagner, MD17; Kevin A. Walter, MD18; Rekha Chaudary, MD19; Samuel A. Goldlust, MD20; Ian Y. Lee, MD21; Daniela A. Bota, MD, PhD22; Heinrich Elinzano, MD23; Jai Grewal, MD24; Kevin Lillehei, MD25; Tom Mikkelsen, MD, FRCPC21; Tobias Walbert, MD21; Steven Abram, MD26; Andrew J. Brenner, MD, PhD27; Matthew G. Ewend, MD28; Simon Khagi, MD29; Darren S. Lovick, MD30; Jana Portnow, MD31; Lyndon Kim, MD32; William G. Loudon, MD33; Nina L. Martinez, MD34; Reid C. Thompson, MD35; David E. Avigan, MD36; Karen L. Fink, MD, PhD37; Francois J. Geoffroy, MD38; Pierre Giglio, MD39; Oleg Gligich, MD40; Dietmar Krex, MD41; Scott M. Lindhorst, MD42; Jose Lutzky, MD43; Hans-Jörg Meisel, MD, PhD44; Minou Nadji-Ohl, MD45; Lhagva Sanchin, MD44; Andrew Sloan, MD46; Lynne P. Taylor, MD47; Julian K. Wu, MD47; Erin M. Dunbar, MD48; Arnold B. Etame, MD, PhD49; Santosh Kesari, MD, PhD50; David Mathieu, MD51; David E. Piccioni, MD, PhD52; David S. Baskin, MD53; Michel Lacroix, MD54; Sven-Axel May, MD55; Pamela Z. New, MD56; Timothy J. Pluard, MD57; Steven A. Toms, MD58; Victor Tse, MD59; Scott Peak, MD59; John L. Villano, MD, PhD60; James D. Battiste, MD, PhD61; Paul J. Mulholland, MD62; Michael L. Pearlman, MD63; Kevin Petrecca, MD, PhD64; Michael Schulder, MD65; Robert M. Prins, PhD66; Alton L. Boynton, PhD67; Marnix L. Bosch, PhD67
Author Affiliations Article Information
JAMA Oncol. Published online November 17, 2022. doi:10.1001/jamaoncol.2022.5370
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Association of DCVax-L With Extension of Survival Among Patients With Glioblastoma
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Key Points
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.
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
Introduction
Glioblastoma is a highly lethal brain cancer, with a nearly 100% recurrence rate and dismal patient survival. Standard of care (SOC) for newly diagnosed glioblastoma (nGBM) includes surgery, radiotherapy, and chemotherapy. Following initial surgery, tumors typically recur in 6 to 8 months,1 median overall survival (mOS) is 15 to 17 months, and 5-year survival is generally less than 5%.2 For recurrent glioblastoma (rGBM), there is no established SOC.3 Among more than 400 clinical trials since 2005, with more than 32 000 patients, testing diverse treatment modalities,4 only 1 phase 3 trial in nGBM and no phase 3 trials in rGBM have demonstrated a survival benefit.5
We report the overall survival (OS) and safety outcomes of a phase 3 nonrandomized controlled trial testing an autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) combined with SOC for treatment of glioblastoma. Dendritic cells present tumor antigens to the immune system, prime T cells, and mobilize antitumor responses.6,7
Many trials, especially for incurable diseases, incorporate a crossover design for feasibility and/or ethical reasons. A crossover was considered necessary when our study began in 2007 to make patient enrollment and retention feasible when novel immunotherapies were not yet generally viewed as promising for cancer. The crossover was also important to justify the placebo group for patients undergoing a leukapheresis—an invasive procedure necessary for blinding and for manufacturing vaccine but offering no benefit to patients in the placebo group if they could not receive their autologous vaccine.
The crossover design necessitated the use of external controls to evaluate OS. Traditional (ie, within-study) randomized control comparisons were infeasible, since most placebo group patients received DCVax-L through the crossover. When randomized clinical trials (RCTs) are not feasible, use of external controls is increasingly recognized as an effective way to enable comparative analyses of outcomes.8 There is also growing support for streamlining trials in the neuro-oncology field.9,10
Methods
Study Design and Oversight
This was originally a phase 3 randomized, double-blind clinical trial, with a crossover design. The trial was conducted at 94 sites in 4 countries (US, Canada, UK, and Germany). The screening and enrollment process and treatment assignment are described in Figure 1A and B.11,12 The trial protocol appears in Supplement 1.
The primary end point was OS in patients with nGBM from the time of randomization (a median of 3.1 months after surgery), and the secondary end point was OS in rGBM from the time of recurrence. Each group was compared with independently selected, contemporaneous, matched external control patients as prespecified in the Statistical Analysis Plan (SAP) (Supplement 1).
The original primary end point in the 2007 study protocol was progression-free survival (PFS) determined by magnetic resonance imaging (MRI). However, while the trial was underway, the difficulty of distinguishing actual disease progression from pseudo-progression comprised of inflammation or necrosis or from vaccine-induced infiltration of immune cells was recognized.13 Accordingly, the SAP for this study focused on OS.
On enrollment, patients were randomized 2:1 to either DCVax-L or placebo, plus SOC. Randomization was performed centrally by independent contract research organizations (CROs [Synteract, Parexel]).
Following tumor recurrence, all patients were allowed to cross over to start or continue receiving DCVax-L. The trial did not prescribe additional surgery at recurrence; the DCVax-L administered to crossover patients after recurrence was the product from the original surgery. All parties remained blinded to the treatment before crossover. Due to the crossover, the placebo group was depleted, and OS was assessed by comparison to external control populations (ECPs).
The protocol was approved by the relevant institutional review boards or ethics committees. The trial was performed in accordance with the Declaration of Helsinki.14 The data were collected and held by independent CROs (Synteract, Parexel) and were analyzed by independent statisticians (Quantics). Patients gave informed consent for tumor collection in presurgery screening and thereafter gave consent for study participation (Figure 1A).
Patients and Study Procedures
Patients aged 18 to 70 years with nGBM (World Health Organization grade 4), Karnofsky Performance Score (KPS) of 70 or greater, life expectancy of 8 or more weeks, and adequate laboratory values were eligible for enrollment (Figure 1A). Patients centrally determined (ICON) to have radiographic evidence of early disease progression15 following radiochemotherapy were excluded.
After initial diagnosis, all patients underwent surgery and collection of tumor tissue for manufacturing of DCVax-L. After surgery, diagnosis of glioblastoma was histologically confirmed centrally (Quest Diagnostics; Mayo Clinic). The MGMT (O6-methylguanine-DNA methyltransferase) gene promoter methylation status, IDH (isocitrate dehydrogenase) R132 mutation status, and postsurgery minimal (<2 cm2) vs significant (≥2 cm2) residual tumor were determined centrally (LabCorp; Mayo; ICON). The KPS was determined by the treating physician.
Patients underwent MRI before enrollment and every 2 months thereafter. Progression was assessed centrally (ICON) on a blinded basis. Adverse events were assessed throughout the study according to National Cancer Institute Common Terminology Criteria version 3.0.17
Patients received either DCVax-L or placebo on days 0, 10, and 20, then in months 2, 4, and 8 and months 12, 18, 24, and 30, with monthly temozolomide as SOC. Each DCVax-L dose comprised 2.5 million DCs injected intradermally in the upper arm, alternating arms between treatment visits. The placebo was unmanipulated peripheral blood mononuclear cells.
External Control Populations
The ECPs were determined by an independent expert firm (York Health Economics Consortium) and comprised patients from the control groups from contemporaneous RCTs closely matched to the current study based on 14 criteria prespecified in the SAP (Supplement 1). These studies met the “fit for purpose” criteria outlined by Mishra-Kalyani et al.8 We compared the treatment groups of the external trials to the ECPs to validate the methodology, applied sensitivity analyses to check for biases, and conducted a matching-adjusted indirect comparison (MAIC)18 to adjust for imbalances in individual patient characteristics (eAppendix 1 in Supplement 2).
Statistical Analysis
Primary End Point: OS in Patients With nGBM
All statistical analyses were conducted in SAS version 9.4 (SAS Institute). The primary end point was OS from randomization to death from any cause in patients with nGBM. The 1-sided significance level was 2.5%. The O’Brien-Fleming group sequential boundary function19 and alpha-spending function of Lan and DeMets20 were used to adjust for sequential testing of OS. The final analysis was conducted at the 1-sided 2.409% level. OS was analyzed using log-rank test at the appropriate α level. The hazard ratio (HR) and confidence intervals were calculated using the proportional hazards model with treatment as covariate. Individual control patient survival data were reconstructed by digitizing the published Kaplan-Meier (KM) curves.16 The algorithm to extract individual patient level data from published KM curves uses as inputs the x- and y-coordinates from digitized KM curves, the reported numbers at risk at various time points (which accounts for censored participants), and the total number of events reported. It then applies an iterative process to reconstruct the KM parameters, from which the individual patient data are obtained. Full details on the method are found in Guyot et al.16
Secondary End Point: OS in Patients With rGBM
For the secondary end point, OS in patients with rGBM was measured from first recurrence to death from any cause. The 1-sided significance level allocated to this end point was 2.5%. OS was analyzed using the log-rank test, and the HR and 95% CIs were calculated as described previously.
Landmark Analyses and KM Survival Curve Tails
The KM estimates of landmark survival rates at 6, 12, 18, 24, 30, 36, 42, 48, 54, and 60 months were calculated along with Hall-Wellner 2-sided 95% CIs21 (adjusted for multiplicity). The numbers of patients available for comparison at late time points was small, especially in the control population, resulting in relatively wide confidence intervals.
Results
Patients and Treatments
From August 2007 to November 2015, 331 patients with nGBM were enrolled (Figure 1B). The median (range) age was 56 (19-73) years, 202 participants (61.0%) were men; 7 (2.1%), Black or African American; 16 (4.8%), Hispanic or Latino; and 294 (88.8%), White. Screening and enrollment were suspended from 2008 through 2011 due to the financial crisis, resumed on a limited basis in 2012, and 303 of the 331 patients (91.5%) were enrolled during 2012 to 2015.
All patients underwent surgical resection, recovery, leukapheresis, and 6 weeks of postoperative SOC radiochemotherapy prior to enrollment (Figure 1A). The median time from surgery to randomization was 3.1 months.
Of the 331 patients, 232 were randomized to initial DCVax-L treatment and 99 to placebo. Following tumor recurrence, 64 of the 99 patients in the placebo group crossed over to receive DCVax-L, while 120 of the 232 patients who had already received DCVax-L continued to receive DCVax-L. The patients, investigators, study team, and sponsor remained blinded to the treatments before crossover.
External Controls
The ECP for the primary end point (OS in nGBM) comprised 1366 patients with nGBM treated with SOC in the control groups of 5 comparator RCTs5,22-25 (eTable 1 in Supplement 2). The ECP for the secondary end point (OS in rGBM) comprised 640 patients with rGBM at first recurrence treated with either SOC therapies (lomustine, bevacizumab, or best supportive care) or a placebo in the control groups of 10 comparator RCTs26-35 (eTable 1 in Supplement 2).
The patient demographic characteristics and prognostic factors of the DCVax-L cohorts were well matched with the ECPs for both the primary and secondary end points, based on the 14 criteria prespecified in the SAP (Table 1; eAppendix and eTable 2 in Supplement 2). The analysis of each of the 15 comparator trials, substituting our ECP for the original control groups, confirmed that the outcomes were the same as originally reported (primary end point met or not met).
In the 5 sensitivity analyses conducted to address potential known and unknown confounders in the nGBM ECP, the HR results (range, 0.77-0.82) were comparable with the HR in all 5 studies included (HR, 0.80). In the sixth sensitivity analysis, dropping 2 of the 5 comparator studies22,23 because it was not clear whether they had excluded patients with early progression, the HR remained the same (0.80 in both). The MAIC analyses adjusted for imbalances in individual patient characteristics between the patients receiving DCVax-L and the nGBM ECPs by applying a weight to each patient in the DCVax-L cohort to result in a match with the patient characteristics of the external populations.
Survival Outcomes
OS in Patients With nGBM
The mOS for patients with nGBM assigned to the DCVax-L cohort at enrollment was 19.3 (95% CI, 17.5-21.3) months from the time of randomization (22.4 months from surgery) compared with 16.5 (95% CI, 16.0-17.5) months from randomization for the 1366-patient ECP (log-rank HR, 0.80; 95% CI, 0.00-0.94; P = .002) (Figure 2A). The data indicate a 20% relative reduction in risk of death at any point in time for patients with nGBM receiving DCVax-L, and this relative survival benefit increased over time (Table 2): 15.7% of patients receiving DCVax-L vs 9.9% of ECP patients were alive at 48 months after randomization, and 13.0% of DCVax-L patients vs 5.7% of ECP patients were alive at 60 months after randomization. The long-term survivors tended to have favorable prognostic characteristics, but these factors did not fully explain the survival observed (eFigure 2 in Supplement 2). The outcome of the MAIC analyses showed that after adjustment for imbalances in individual patient characteristics the difference in OS between the DCVax-L cohort and the ECP was still significant.
Six prespecified subgroup analyses were conducted (Figure 2B and eFigure 1 in Supplement 2). Patients receiving DCVax-L had HRs less than 1 in all subgroups, and the difference was statistically significant for 4 of the 6 subgroups at the 95% confidence level, and for 3 of the 6 subgroups when multiplicity correction was applied. In patients with nGBM with methylated MGMT, mOS was 30.2 (95% CI, 23.7-33.9) months from randomization (33.0 months from surgery) in 90 patients receiving DCVax-L vs 21.3 (95% CI, 18.3-25.1) months in the 199 patients in the ECP (HR, 0.74; 95% CI, 0.55-1.00, P = .03).
OS in Patients With rGBM
The 64 patients with rGBM who received DCVax-L after recurrence had mOS of 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months in the ECP (HR, 0.58; 0.00-0.76; P < .001) (Figure 3). These data indicate a 42% relative reduction in risk of death at any point in time for patients with rGBM treated with DCVax-L at first recurrence, and this survival benefit continued over time (Table 2): 20.7% of the patients receiving DCVax-L vs 9.6% of the patients in the ECP were alive at 24 months after recurrence, and 11.1% vs 5.1% were alive at 30 months after recurrence.
Postprogression Treatments
The trial design did not prescribe a second surgery on recurrence, and most patients did not have a second surgery. Only 18 of the 64 patients in the placebo group (28.1%) who crossed over to start receiving DCVax-L after progression as patients with rGBM had any surgery beyond the original tumor resection when newly diagnosed. The patients who had additional surgery had shorter survival than patients who had no additional surgery (postprogression mOS of 11.8 [95% CI, 8.5-14.7] months vs 13.4 [95% CI, 7.7-19.3] months). For all crossover patients, the DCVax-L vaccines administered after progression were the products made after the original surgery. No new DCVax-L vaccines were made following any postprogression surgery.
The trial design allowed additional treatments during the postrecurrence crossover period. Among the 232 patients in the DCVax-L group, 22 received bevacizumab and lomustine (9.5%), 65 (28.0%) received only bevacizumab, and 15 (6.5%) received only lomustine. Participants who received bevacizumab had shorter survival times than those who did not (16.4 [95% CI, 14.2-18.6] vs 22.1 [95% CI, 19.4-24.9] months). There was no significant survival difference between participants who received lomustine vs those who did not (18.6 [95% CI, 13.6-23.6] vs 19.3 [95% CI, 16.8-21.7] months).
Eight of the 232 patients (3.4%) receiving DCVax-L were treated with tumor-treating fields (TTF) following recurrence. Four of those 8 patients (50.0%) continued receiving DCVax-L while using the TTF device after recurrence and survived from 22.6 to more than 72.7 months from randomization. Four of the 8 patients (50.0%) stopped receiving DCVax-L while using the TTF device post-recurrence, and survived from 8.9 to 29.2 months from randomization.
Progression-Free Survival
The PFS end point became infeasible for this trial due to the challenges now well recognized in trying to distinguish true progression from pseudo-progression (including vaccine-induced immune cell infiltration).13 There were 494 imaging time points when possible progression was observed by the independent radiologists, and 256 of these (>50%) required adjudication due to discordant interpretations. Based on these assessments, the median PFS was 6.2 (95% CI, 5.7-7.4) months for patients receiving DCVax-L and 7.6 (95% CI, 5.6-10.9) months for the placebo group. This difference was not statistically significant (P = .47).
Safety and Toxic Effects
The DCVax-L was well tolerated. Of 2151 total doses of DCVax-L administered, only 5 serious adverse events were deemed at least possibly related to the investigational treatment. There were 3 cases of intracranial edema (2 at grade 3; 1 at grade 2), 1 case of nausea (grade 3), and 1 case of lymph node infection (grade 3). There was no evidence of any auto-immune reactions or cytokine storm among patients who received DCVax-L.
Discussion
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.
Limitations
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
Conclusions
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.
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Article Information
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.
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Ellingson BM, Chung C, Pope WB, Boxerman JL, Kaufmann TJ. Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape. J Neurooncol. 2017;134(3):495-504. doi:10.1007/s11060-017-2375-2PubMedGoogle ScholarCrossref
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World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053.
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Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8(7):1277-1280. doi:10.1200/JCO.1990.8.7.1277PubMedGoogle ScholarCrossref
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Guyot P, Ades AE, Ouwens MJ, Welton NJ. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12:9. doi:10.1186/1471-2288-12-9PubMedGoogle ScholarCrossref
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Common Terminology Criteria for Adverse events v3.0 (CTCAE). August 9, 2009. Accessed October 10, 2022. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf
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Signorovitch JE, Sikirica V, Erder MH, et al. Matching-adjusted indirect comparisons: a new tool for timely comparative effectiveness research. Value Health. 2012;15(6):940-947. doi:10.1016/j.jval.2012.05.004PubMedGoogle ScholarCrossref
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O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549-556. doi:10.2307/2530245PubMedGoogle ScholarCrossref
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Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 1983;70(3):659-663. doi:10.2307/2336502Google ScholarCrossref
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Hall WJ, Wellner JA. Confidence bands for a survival curve from censored data. Biometrika. 1980;67(1):133-143. doi:10.1093/biomet/67.1.133Google ScholarCrossref
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Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):699-708. doi:10.1056/NEJMoa1308573PubMedGoogle ScholarCrossref
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Gilbert MR, Wang M, Aldape KD, et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31(32):4085-4091. doi:10.1200/JCO.2013.49.6968PubMedGoogle ScholarCrossref
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Weller M, Butowski N, Tran DD, et al; ACT IV trial investigators. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18(10):1373-1385. doi:10.1016/S1470-2045(17)30517-XPubMedGoogle ScholarCrossref
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Wen PY, Reardon DA, Armstrong TS, et al. A randomized double-blind placebo-controlled phase II trial of dendritic cell vaccine ICT-107 in newly diagnosed patients with glioblastoma. Clin Cancer Res. 2019;25(19):5799-5807. doi:10.1158/1078-0432.CCR-19-0261PubMedGoogle ScholarCrossref
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Brandes AA, Carpentier AF, Kesari S, et al. A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro Oncol. 2016;18(8):1146-1156. doi:10.1093/neuonc/now009PubMedGoogle ScholarCrossref
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Brandes AA, Gil-Gil M, Saran F, et al. A randomized phase II trial (TAMIGA) evaluating the efficacy and safety of continuous bevacizumab through multiple lines of treatment for recurrent glioblastoma. Oncologist. 2019;24(4):521-528. doi:10.1634/theoncologist.2018-0290PubMedGoogle ScholarCrossref
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Cloughesy T, Finocchiaro G, Belda-Iniesta C, et al. Randomized, double-blind, placebo-controlled, multicenter phase II study of onartuzumab plus bevacizumab versus placebo plus bevacizumab in patients with recurrent glioblastoma: efficacy, safety, and hepatocyte growth factor and o6-methylguanine-DNA methyltransferase biomarker analyses. J Clin Oncol. 2017;35(3):343-351. doi:10.1200/JCO.2015.64.7685PubMedGoogle ScholarCrossref
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Narita Y, Arakawa Y, Yamasaki F, et al. A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma. Neuro Oncol. 2019;21(3):348-359. doi:10.1093/neuonc/noy200PubMedGoogle ScholarCrossref
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Taal W, Oosterkamp HM, Walenkamp AM, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol. 2014;15(9):943-953. doi:10.1016/S1470-2045(14)70314-6PubMedGoogle ScholarCrossref
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Wick W, Gorlia T, Bendszus M, et al. Lomustine and bevacizumab in progressive glioblastoma. N Engl J Med. 2017;377(20):1954-1963. doi:10.1056/NEJMoa1707358PubMedGoogle ScholarCrossref
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Wick W, Puduvalli VK, Chamberlain MC, et al. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 2010;28(7):1168-1174. doi:10.1200/JCO.2009.23.2595PubMedGoogle ScholarCrossref
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Whiteside TL. Immune responses to malignancies. J Allergy Clin Immunol. 2010;125(2)(suppl 2):S272-S283. doi:10.1016/j.jaci.2009.09.045PubMedGoogle ScholarCrossref
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Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11(15):5515-5525. doi:10.1158/1078-0432.CCR-05-0464PubMedGoogle ScholarCrossref
38.
Prins RM, Soto H, Konkankit V, et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res. 2011;17(6):1603-1615. doi:10.1158/1078-0432.CCR-10-2563PubMedGoogle ScholarCrossref
39.
Antonios JP, Soto H, Everson RG, et al. PD-1 blockade enhances the vaccination-induced immune response in glioma. JCI Insight. 2016;1(10):e87059. doi:10.1172/jci.insight.87059PubMedGoogle ScholarCrossref
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Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. doi:10.1056/NEJMoa043331PubMedGoogle ScholarCrossref
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McDonald KL, Tabone T, Nowak AK, Erber WN. Somatic mutations in glioblastoma are associated with methylguanine-DNA methyltransferase methylation. Oncol Lett. 2015;9(5):2063-2067. doi:10.3892/ol.2015.2980PubMedGoogle ScholarCrossref
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van Thuijl HF, Mazor T, Johnson BE, et al. Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment. Acta Neuropathol. 2015;129(4):597-607. doi:10.1007/s00401-015-1403-6PubMedGoogle ScholarCrossref
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Now since the journal is published, the company can open its mouth:
News provided by
Northwest Biotherapeutics
Nov 17, 2022, 12:36 ET
Both Median Survival and "Long Tail" of Extended Survival Were Increased In Both Newly Diagnosed and Recurrent Glioblastoma
Results Featured In JAMA Oncology Peer Reviewed Publication
BETHESDA, Md., Nov. 17, 2022 /PRNewswire/ -- Northwest Biotherapeutics (OTCQB: NWBO) ("NW Bio"), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, today reported that in its Phase III clinical trial both median survival and the "long tail" of extended survival were increased in both newly diagnosed and recurrent glioblastoma brain cancer patients treated with DCVax®-L. The trial has met both the primary and the secondary endpoint under the Statistical Analysis Plan for the trial.
The trial results were reported today in a featured publication co-authored by more than 70 physicians from leading institutions across the U.S., Canada, U.K. and Germany, in the peer reviewed cancer journal JAMA Oncology, entitled "Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination with Extension of Survival Among Patients with Newly Diagnosed and Recurrent Glioblastoma". https://jamanetwork.com/journals/jamaoncology/fullarticle/2798847
The Company believes this is the first time in nearly 20 years that a Phase III trial of a systemic treatment has shown such survival extension in newly diagnosed glioblastoma, and the first time in nearly 30 years that a Phase III trial of any type of treatment has shown such survival extension in recurrent glioblastoma.
Ms. Powers, CEO of NW Bio, commented: "We are excited to see the meaningful survival extensions in glioblastoma patients treated with DCVax®-L in this trial – particularly in the "long tail" of the survival curve, where we see more than double the survival rates as with existing standard of care. With well over 400 clinical trials for glioblastoma having failed over the last 15 years, it is gratifying to be able to offer new hope to patients who face this devastating disease."
"It is especially encouraging to see these survival extensions with a treatment that has such a benign safety profile" Ms. Powers continued. "Over 2,100 doses of DCVax-L were administered during the trial, and we found that the adverse event profile was not meaningfully different than with standard of care alone. DCVax-L is also quite simple for the physician and patient: just an intradermal injection in the upper arm, 6 times over the course of year 1, and then twice a year for maintenance thereafter."
Glioblastoma is the most common and most lethal form of primary brain cancer. Standard of care (SOC) treatments have been virtually unchanged for nearly 20 years. With SOC treatments, patients typically survive for only about 15-17 months from diagnosis, with the tumor recurring at about 6-8 months from diagnosis and the patients typically surviving for about 7-9 months after recurrence. Five-year survival from diagnosis is only about 5%.
In the Phase III trial of DCVax®-L, median Overall Survival (mOS) for newly diagnosed GBM patients (n=232) was 19.3 months from randomization (22.4 months from surgery) with DCVax-L vs. 16.5 months from randomization in the controls (HR=0.80, p=0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For recurrent GBM (n=64), mOS was 13.2 months from relapse vs. 7.8 months (HR = 0.58, p<0.001). Survival at 24 and 30 months post-recurrence was 20.7% vs. 9.6%, and 11.1% vs 5.1%, respectively. In newly diagnosed GBM patients with methylated MGMT, mOS was 30.2 months from randomization (33 months from surgery) with DCVax-L (n=90) vs. 21.3 months in controls (n=199) (HR=0.74, p=0.027).
From a safety perspective, out of more than 2,100 doses of DCVax-L administered during the Phase III trial, there were only 5 serious adverse events that were deemed at least possibly related to the treatment. There were 3 cases of intracranial edema, 1 case of nausea and 1 case of lymph node infection.
DCVax-L is a fully personalized immune therapy made from a patient's own immune cells (dendritic cells) and antigens (biomarkers) from a sample of the patient's own tumor. A multi-year set of doses is produced in a single manufacturing batch, which takes 8 days. The product is then stored frozen in individual doses, and is "off the shelf" throughout the treatment regimen. The doses are stored centrally and simply taken out of the freezer and delivered to the physician when needed for the patient's next treatment.
Dr. Marnix Bosch, senior author on the publication, concluded "This DCVax-L trial, at 94 hospitals in 4 countries, involved the teamwork of a large number of dedicated investigators. Publication of the results in the prestigious, peer-reviewed journal JAMA Oncology honors this teamwork and demonstrates how the field can move forward with novel therapies and innovative clinical trial designs."
The Company is currently working on preparations for applications for regulatory approval of DCVax®-L.
About Northwest Biotherapeutics
Northwest Biotherapeutics is a biotechnology company focused on developing personalized immunotherapy products designed to treat cancers more effectively than current treatments, without toxicities of the kind associated with chemotherapies, and on a cost-effective basis, in both North America and Europe. The Company has a broad platform technology for DCVax® dendritic cell-based vaccines. The Company's lead program is a 331-patient Phase III trial of DCVax®-L for newly diagnosed Glioblastoma multiforme (GBM). GBM is the most aggressive and lethal form of brain cancer, and is an "orphan disease." This Phase III trial has been completed and top line data was presented by a key investigator at a recent scientific meeting. The Company also plans to pursue development of DCVax®-Direct for inoperable solid tumor cancers. It has completed a 40-patient Phase I trial and plans to prepare for Phase II trials as resources permit. The Company previously conducted a Phase I/II trial with DCVax-L for advanced ovarian cancer together with the University of Pennsylvania.
Disclaimer
Statements made in this news release that are not historical facts, including statements concerning future treatment of patients using DCVax and future clinical trials, are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "expect," "believe," "intend," "design," "plan," "continue," "may," "will," "anticipate," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We cannot guarantee that we actually will achieve the plans, intentions or expectations disclosed in our forward-looking statements and you should not place undue reliance on our forward-looking statements. Actual results may differ materially from those projected in any forward-looking statement. Specifically, there are a number of important factors that could cause actual results to differ materially from those anticipated, such as risks related to the Company's ability to enroll patients in its clinical trials and complete the trials on a timely basis, uncertainties about the clinical trials process, uncertainties about the timely performance of third parties, risks related to whether the Company's products will demonstrate safety and efficacy, risks related to the Company's ongoing ability to raise additional capital, and other risks included in the Company's Securities and Exchange Commission ("SEC") filings. Additional information on the foregoing risk factors and other factors, including Risk Factors, which could affect the Company's results, is included in its SEC filings. Finally, there may be other factors not mentioned above or included in the Company's SEC filings that may cause actual results to differ materially from those projected in any forward-looking statement. The Company assumes no obligation to update any forward-looking statements as a result of new information, future events or developments, except as required by securities laws.
Northwest Biotherapeutics Reports Positive Top-Line Results From Phase 3 Trial of DCVax®-L for Glioblastoma
News provided by
Northwest Biotherapeutics
Nov 17, 2022, 12:36 ET
Both Median Survival and "Long Tail" of Extended Survival Were Increased In Both Newly Diagnosed and Recurrent Glioblastoma
Results Featured In JAMA Oncology Peer Reviewed Publication
BETHESDA, Md., Nov. 17, 2022 /PRNewswire/ -- Northwest Biotherapeutics (OTCQB: NWBO) ("NW Bio"), a biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, today reported that in its Phase III clinical trial both median survival and the "long tail" of extended survival were increased in both newly diagnosed and recurrent glioblastoma brain cancer patients treated with DCVax®-L. The trial has met both the primary and the secondary endpoint under the Statistical Analysis Plan for the trial.
The trial results were reported today in a featured publication co-authored by more than 70 physicians from leading institutions across the U.S., Canada, U.K. and Germany, in the peer reviewed cancer journal JAMA Oncology, entitled "Association of Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination with Extension of Survival Among Patients with Newly Diagnosed and Recurrent Glioblastoma". https://jamanetwork.com/journals/jamaoncology/fullarticle/2798847
The Company believes this is the first time in nearly 20 years that a Phase III trial of a systemic treatment has shown such survival extension in newly diagnosed glioblastoma, and the first time in nearly 30 years that a Phase III trial of any type of treatment has shown such survival extension in recurrent glioblastoma.
Ms. Powers, CEO of NW Bio, commented: "We are excited to see the meaningful survival extensions in glioblastoma patients treated with DCVax®-L in this trial – particularly in the "long tail" of the survival curve, where we see more than double the survival rates as with existing standard of care. With well over 400 clinical trials for glioblastoma having failed over the last 15 years, it is gratifying to be able to offer new hope to patients who face this devastating disease."
"It is especially encouraging to see these survival extensions with a treatment that has such a benign safety profile" Ms. Powers continued. "Over 2,100 doses of DCVax-L were administered during the trial, and we found that the adverse event profile was not meaningfully different than with standard of care alone. DCVax-L is also quite simple for the physician and patient: just an intradermal injection in the upper arm, 6 times over the course of year 1, and then twice a year for maintenance thereafter."
Glioblastoma is the most common and most lethal form of primary brain cancer. Standard of care (SOC) treatments have been virtually unchanged for nearly 20 years. With SOC treatments, patients typically survive for only about 15-17 months from diagnosis, with the tumor recurring at about 6-8 months from diagnosis and the patients typically surviving for about 7-9 months after recurrence. Five-year survival from diagnosis is only about 5%.
In the Phase III trial of DCVax®-L, median Overall Survival (mOS) for newly diagnosed GBM patients (n=232) was 19.3 months from randomization (22.4 months from surgery) with DCVax-L vs. 16.5 months from randomization in the controls (HR=0.80, p=0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For recurrent GBM (n=64), mOS was 13.2 months from relapse vs. 7.8 months (HR = 0.58, p<0.001). Survival at 24 and 30 months post-recurrence was 20.7% vs. 9.6%, and 11.1% vs 5.1%, respectively. In newly diagnosed GBM patients with methylated MGMT, mOS was 30.2 months from randomization (33 months from surgery) with DCVax-L (n=90) vs. 21.3 months in controls (n=199) (HR=0.74, p=0.027).
From a safety perspective, out of more than 2,100 doses of DCVax-L administered during the Phase III trial, there were only 5 serious adverse events that were deemed at least possibly related to the treatment. There were 3 cases of intracranial edema, 1 case of nausea and 1 case of lymph node infection.
DCVax-L is a fully personalized immune therapy made from a patient's own immune cells (dendritic cells) and antigens (biomarkers) from a sample of the patient's own tumor. A multi-year set of doses is produced in a single manufacturing batch, which takes 8 days. The product is then stored frozen in individual doses, and is "off the shelf" throughout the treatment regimen. The doses are stored centrally and simply taken out of the freezer and delivered to the physician when needed for the patient's next treatment.
Dr. Marnix Bosch, senior author on the publication, concluded "This DCVax-L trial, at 94 hospitals in 4 countries, involved the teamwork of a large number of dedicated investigators. Publication of the results in the prestigious, peer-reviewed journal JAMA Oncology honors this teamwork and demonstrates how the field can move forward with novel therapies and innovative clinical trial designs."
The Company is currently working on preparations for applications for regulatory approval of DCVax®-L.
About Northwest Biotherapeutics
Northwest Biotherapeutics is a biotechnology company focused on developing personalized immunotherapy products designed to treat cancers more effectively than current treatments, without toxicities of the kind associated with chemotherapies, and on a cost-effective basis, in both North America and Europe. The Company has a broad platform technology for DCVax® dendritic cell-based vaccines. The Company's lead program is a 331-patient Phase III trial of DCVax®-L for newly diagnosed Glioblastoma multiforme (GBM). GBM is the most aggressive and lethal form of brain cancer, and is an "orphan disease." This Phase III trial has been completed and top line data was presented by a key investigator at a recent scientific meeting. The Company also plans to pursue development of DCVax®-Direct for inoperable solid tumor cancers. It has completed a 40-patient Phase I trial and plans to prepare for Phase II trials as resources permit. The Company previously conducted a Phase I/II trial with DCVax-L for advanced ovarian cancer together with the University of Pennsylvania.
Disclaimer
Statements made in this news release that are not historical facts, including statements concerning future treatment of patients using DCVax and future clinical trials, are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "expect," "believe," "intend," "design," "plan," "continue," "may," "will," "anticipate," and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We cannot guarantee that we actually will achieve the plans, intentions or expectations disclosed in our forward-looking statements and you should not place undue reliance on our forward-looking statements. Actual results may differ materially from those projected in any forward-looking statement. Specifically, there are a number of important factors that could cause actual results to differ materially from those anticipated, such as risks related to the Company's ability to enroll patients in its clinical trials and complete the trials on a timely basis, uncertainties about the clinical trials process, uncertainties about the timely performance of third parties, risks related to whether the Company's products will demonstrate safety and efficacy, risks related to the Company's ongoing ability to raise additional capital, and other risks included in the Company's Securities and Exchange Commission ("SEC") filings. Additional information on the foregoing risk factors and other factors, including Risk Factors, which could affect the Company's results, is included in its SEC filings. Finally, there may be other factors not mentioned above or included in the Company's SEC filings that may cause actual results to differ materially from those projected in any forward-looking statement. The Company assumes no obligation to update any forward-looking statements as a result of new information, future events or developments, except as required by securities laws.
GlobeCitizen
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Bought back all shares sold this morning below $1.
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Yes doc. I had said this years ago on the first day I initiated this thread.
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Vaccine doubles brain tumour survival rate in medical breakthrough
Research showed that 13 per cent of vaccine patients with the most aggressive form of glioblastoma were still alive after five years
Vaccine doubles brain tumour survival rate in medical breakthrough
Research showed that 13 per cent of vaccine patients with the most aggressive form of glioblastoma were still alive after five years
www.telegraph.co.uk
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You are right Henri. Congratulations on your resolve of holding your position for so long. Now the results are validated by the most prestigious oncology journal in the world, the JAMA Oncology. Better things to come in the years ahead. The share price is still in its infancy today. Stay strong!
Btw, one combo trial at UCLA shows 50% patients participating in the trial have lived 10 years, yes TEN YEARS! I guess it's because the nature of the trial in both scales and stages, it may need to expand into the next stage.
btw2, a friend told me Etrade put NWBO status as "in Play" which means there may be potential deals in the making.
Btw, one combo trial at UCLA shows 50% patients participating in the trial have lived 10 years, yes TEN YEARS! I guess it's because the nature of the trial in both scales and stages, it may need to expand into the next stage.
btw2, a friend told me Etrade put NWBO status as "in Play" which means there may be potential deals in the making.
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had one bottle of 茅台 tonight with family and friends celebrating validation of DCVax-L (Murcidencel) results validated by peer-reviewed journal (JAMA Ontology) which has only about 4% of accepting rate, particularly its endorsement that the results are both clinically meaningful and statistically significant.
The share price is nothing at this point. It will match up with its full potential in the future.
The share price is nothing at this point. It will match up with its full potential in the future.
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GlobeCitizen
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Perhaps 还是茅台，just more aged. 自从我起了此楼我已经喝了八瓶茅台了，高兴也喝不高兴也喝。现在还有几瓶太老了不敢喝。 老婆说我没有money sense，我不得不认。更不要说无数的cabernets, and Canadian whiskey.
Cheer!
Cheer!
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