An international Phase III study led by researchers at the University of California – Los Angeles (UCLA) and at Northwest Biotherapeutics Inc has found that a personalised glioblastoma vaccine may increase long-term survival in some patients. Nearly 30% of patients in the current trial have now survived at least three years post-enrolment, with patients continuing to be followed over time.
The vaccine, known as DCVax-L, uses a patient's own dendritic cells to help activate the immune system to fight cancer. Currently, median survival for glioblastoma is 15 to 17 months, and less than 5% of glioblastoma patients who receive standard care survive five years.
These are interim findings from the study, which is still in progress. The study is the largest trial to date testing a customised vaccine in patients diagnosed with the deadly brain cancer.
"The survival rate is quite remarkable compared to what would be expected for glioblastoma," said lead author Dr Linda Liau, chair of the neurosurgery department at the David Geffen School of Medicine at UCLA and a member of the UCLA Jonsson Comprehensive Cancer Centre. "What's particularly impressive about immunotherapy trials is that there seems to be a population of about 20% to 30% of patients who are living significantly longer than expected – the long tail of the survival curve. And those are the people in whom we think there may be a particularly strong immune response against their cancer that is protecting them from getting tumour reoccurrence."
The vaccine was administered in newly diagnosed glioblastoma patients – at 80 sites across the globe – from July 2007 through November 2015. All patients underwent standard care therapy (surgery to resect the tumour, followed by chemoradiotherapy) before participating in the trial.
After standard care therapy, patients were randomised into two arms of the trial. The first group (232 patients) continued to receive standard care and DCVax-L; the second group (99 patients) received standard care and a placebo treatment. All patients were allowed to receive the vaccine following tumour progression or recurrence. Due to the crossover design of the trial, nearly 90% of the patients received the vaccine.
Researchers found that when analysing all the patients in both arms of the trial (the intent to treat population), median survival is 23.1 months, which is eight months longer than the current median survival time from historical studies using standard of care chemoradiation alone.
Of those who were enrolled more than three years before the data analysis date of this publication, 67 patients (30% of the total) survived for more than 30 months, and 44 (24.2%) survived for more than 36 months. These patients are expected to have a median survival of 46.5 to 88.2 months. At the time of the analysis, 108 of the 331 patients enrolled in the trial (32.6%) were still alive.
Researchers at UCLA have spent almost two decades working to activate dendritic cells against brain cancer. Dendritic cells are a type of white blood cell that typically alerts the immune system when it detects a foreign invader. Liau and her team were the first to test a dendritic cell-based vaccine in patients with glioblastoma, a type of tumour that had previously been thought to be immune-privileged, meaning the immune system won't attack it. However, Liau and her colleagues were able to demonstrate in previous studies that the body could actually mount an immune response against tumours in the brain following the vaccination.
"The unique thing about the DCVax-L vaccine is that this doesn't target a single antigen," Liau said. "This treatment actually uses the patient's own tumour specimen to make the vaccine. This is really a form of personalized immunotherapy that is customised to an individual patient and his/her tumour." The vaccine works by combining brain tumour tissue lysate removed during a patient's surgery with dendritic immune cells drawn from his or her blood. The dendritic cells are activated in the lab to turn against the tumour cells and then injected back into the patient, activating his or her T cells to attack the tumour. In short, the vaccine teaches the immune system to battle the cancer.
Because patients on the trial are living longer than what has been historically expected, the study groups are still blinded and researchers are continuing to monitor the patients to assess the ultimate difference in long-term survival. At that point, they'll issue a final report.
Liau and her colleagues are also in the process of developing new therapies that combine the vaccine and other treatments, with new clinical trials expected to be open in the near future.
Research was supported by Northwest Biotherapeutic Inc and the UCLA SPORE in Brain Cancer.
Abstract
Background: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma.
Methods: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).
Results: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone.
Conclusions: Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival.
Authors
Linda M Liau, Keyoumars Ashkan, David D Tran, Jian L Campian, John E Trusheim, Charles S Cobbs, Jason A Heth, Michael Salacz, Sarah Taylor, Stacy D D’Andre, Fabio M Iwamoto, Edward J Dropcho, Yaron A Moshel, Kevin A Walter, Clement P Pillainayagam, Robert Aiken, Rekha Chaudhary, Samuel A Goldlust, Daniela A Bota, Paul Duic, Jai Grewal, Heinrich Elinzano, Steven A Toms, Kevin O Lillehei, Tom Mikkelsen, Tobias Walpert, Steven R Abram, Andrew J Brenner, Steven Brem, Matthew G Ewend, Simon Khagi, Jana Portnow, Lyndon J Kim, William G Loudon, Reid C Thompson, David E Avigan, Karen L Fink, Francois J Geoffroy, Scott Lindhorst, Jose Lutzky, Andrew E Sloan, Gabriele Schackert, Dietmar Krex, Hans-Jorg Meisel, Julian Wu, Raphael P Davis, Christopher Duma, Arnold B Etame, David Mathieu, Santosh Kesari, David Piccioni, Manfred Westphal, David S Baskin, Pamela Z New, Michel Lacroix, Sven-Axel May, Timothy J Pluard, Victor Tse, Richard M Green, John L Villano, Michael Pearlman, Kevin Petrecca, Michael Schulder, Lynne P Taylor, Anthony E Maida, Robert M Prins, Timothy F Cloughesy, Paul Mulholland, Marnix L Bosch
[link url="https://www.uclahealth.org/personalized-vaccine-may-increase-longterm-survival-in-people-with-deadliest-form-of-brain-cancer"]University of California – Los Angeles Health Sciences material[/link]
[link url="https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6"]Journal of Translational Medicine abstract[/link]