Vaccine confers ‘substantial’ PFS benefit in glioblastoma
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A personalized cancer vaccine conferred a PFS benefit to a subset of patients with newly diagnosed glioblastoma, according to phase 2 study results presented at Society for the Immunotherapy of Cancer Annual Meeting.
Patients with primary glioblastoma who had methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene promoters, as well as those who had mutation of the gene for isocitrate dehydrogenase (IDH), derived “a substantial and similar” benefit when they received AV-GMB-1 (AiVita Biomedical) in addition to standard aggressive therapy, Daniela A. Bota, MD, PhD, medical director of the neuro-oncology program and professor of neurology at University of California, Irvine School of Medicine, and colleagues concluded.
However, the regimen did not lead to a substantial benefit in OS compared with historical results.
“Immunotherapy is currently changing the standard of care for many diseases; however, it has not been very effective at improving survival for patients with glioblastoma,” Bota told Healio. “Previous studies of immune checkpoint inhibitors in both newly diagnosed and recurrent glioblastoma have failed to show a survival benefit.”
AV-GBM-1 is an autologous vaccine given administered after standard therapy for glioblastoma. This may include surgical resection followed by the combination of radiotherapy and temozolomide (Temodar; Merck).
The vaccine comprises autologous dendritic cells loaded with autologous tumor-associated antigens derived from a short-term cell line of self-renewing autologous tumor cells.
Patients in the study received subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24, with doses suspended in 500 mcg granulocyte-macrophage colony-stimulating factor.
The study followed a unique approach, Bota said, in that it used dendritic cells with antigens derived from glioblastoma stem cells, or tumor-initiating cells.
Regardless of the standard therapy used, stem cells are resistant to treatment and, therefore, are not completely eradicated by any established therapy. This leads to tumor recurrence and treatment resistance.
The study has enrolled 60 patients (median age, 59 years; range, 29-70; 70% men; 72% white) on an intent-to-treat basis, and 57 had received at least one injection.
Researchers classified 20 patients (33%) as MGMT methylated, and seven patients (12%) had IDH mutations. Twenty-five patients (42%) were positive for one or both prognostic markers.
An OS rate of 75% or higher 14.6 months from intent-to-treat enrollment served as the study’s primary endpoint. PFS from intent-to-treat enrollment and from first vaccine injection served as secondary endpoints.
Minimum follow-up was 15.2 months.
Researchers reported median OS from intent-to-treat enrollment of 16 months (95% CI, 13-21.3). OS rates from intent-to-treat enrollment were 71.5% at 12 months, 44.2% at 18 months and 24.3% at 24 months.
Median PFS from intent-to-treat enrollment was 10.3 months (95% CI, 8.5-11.6) — approximately 50% longer than reported in randomized clinical trials with comparable standard therapy arms, according to the investigators. Median PFS from first vaccine injection was 8.3 months (95% CI, 6.5-9), or approximately 107% longer than reported in randomized trials.
A subset analysis showed median OS had not been reached for patients with a methylated MGMT promotor or those with an IDH mutation.
Conversely, researchers reported OS of 14.6 months for 38 patients with unmethylated MGMT promoter (P = .026), 14.7 months for 53 patients with IDH wild-type disease (P = .044), and 14.6 months for 35 patients who had neither (P = .017).
Researchers reported higher 18-month survival among patients with a methylated MGMT promoter (59% vs 35%) or IDH mutation (71% vs 40%), as well as among patients who were positive for either prognostic marker (58% vs 32%).
“We are seeing clinically meaningful responses, and we are seeing them in a good number of patients,” Bota told Healio, “The 50% increase in median PFS seen in the study was encouraging, but it did not translate into a substantial increase in OS, perhaps because of discontinuation of treatment after 8 months.”
Bota said she is reassured that the vaccine can be a life-prolonging treatment because nearly one-quarter of patients in the study remained alive 30 months or longer after treatment, including 21 patients who remained alive and in follow-up 15.2 months to 31.7 months from intent-to-treat enrollment.
Safety results showed no grade 3 or grade 4 treatment-related adverse events related to the vaccine administration.
The most frequent vaccine-related adverse events included injection-site reaction (15.8%) and flu-like symptoms (10.5%). The most frequent treatment-related adverse events included fatigue (54.4%), headache (36.8%) and seizure (33%).
The seizure rate in the study appeared higher than those observed in other randomized trials that used comparable standard treatment arms, according to the investigators. The results suggested that the vaccine “may have induced an immune response that increased inflammation at the tumor site” and led to seizures in some patients, Bota and colleagues wrote.
“The treatment remains very safe and feasible, and we have thus far been able to produce a vaccine for more than 90% of patients,” Bota told Healio.
The vaccine’s manufacturer is collaborating with study investigators, who are in discussions with the FDA about moving this research into a phase 3 trial.
"Although they are early, we have seen promising data for the treatment's impact on progression-free survival and, potentially, overall survival,” Bota said.
References:
Bota DA, et al. Abstract 331. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 10-14, 2021; Washington, D.C.
Bota DA, et al. Abstract 952. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 10-14, 2021; Washington, D.C.
Piccioni DE, et al. Abstract 336. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 10-14, 2021; Washington, D.C.
Perspective
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Frederick F. Lang, MD, FACS, FAANS, FAAAS
Glioblastoma remains one of the most recalcitrant cancers to treat, and available therapies result in median survival of just over 1 year. Even immunotherapies, which have been very effective in other cancers, have proven to be ineffective in glioblastoma.
To address these poor outcomes, Bota and colleagues tested AV-GBM-1 in a single-arm, multicenter phase 2 trial of patients with newly diagnosed glioblastoma. The investigators showed they could manufacture and distribute this vaccine, despite the short turnaround time for harvesting and pulsing dendritic cells.
Although researchers reported longer PFS, median OS did not increase substantially compared with historical controls (16 months vs. 14.6 months).
Bota and colleagues are to be congratulated for completing this complex study and for exploring this approach in patients with newly diagnosed disease. Although the investigators state that the minimal improvement in survival may be related to stopping treatment after eight doses, it is also possible that he survival outcome points to the complexity of the immune-cell/tumor-cell interactions in glioblastoma, and the need in the field for fundamental studies defining the underlying regulators of the immune system in the brain and specific to this disease.
Although AV-GBM-1 drives the effector arm of the immune system, resistance mechanisms that result in immune cell inhibition and exhaustion may be limiting the approach.
Detailed immune profiling of tumors at recurrence hopefully were part of this study. These biological analyses would be helpful to define the mechanisms driving recurrence after treatment with AV-GBM-1 and could suggest rationale combinations of AV-GBM-1 with agents that overcome immune inhibition.
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Bota DA, et al. Abstract 952. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 10-14, 2021; Washington, D.C.
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