Dendritic Vaccine Improves Survival in Recurrent Glioblastoma

Andrew T. Parsa, MD, PhD

Chair, Neurological Surgery

Northwestern Memorial Hospital

Chair, Department of Neurological Surgery

Feinberg School of Medicine

Northwestern University

Chicago, IL

A personalized vaccine being tested as a therapy for recurrent glioblastoma multiforme (GBM) improved patient survival compared with standard treatments, according results of a study published in Neuro-Oncology¹ that will help move the agent forward in clinical development.

The therapy tested in the multicenter, singlearm phase II trial was heat-shock protein peptide complex-96 (HSPPC-96), an autologous treatment made from dendritic cells extracted from patient’s tumor tissue after surgical resection with the aim of killing any tumor cells left behind. The vaccine contains a precise antigenic fingerprint of the patient’s cancer, and only targets cells with this fingerprint, greatly reducing the risk of off-target effects.

HSPPC-96 is part of the Prophage Series G-200 vaccine candidates, which have been funded in various studies by the National Cancer Institute and brain research advocacy organizations, according to Agenus Inc, the pharmaceutical developer. The Feinberg School of Medicine at Northwestern University is leading the research effort.

The vaccine’s results compare favorably with historical outcomes of patients with GBM, whose median survival is 15 months from time of diagnosis and 3 to 6 months after recurrence, Bloch et al reported.¹ Chemotherapy and radiation following surgery are standard treatments for newly diagnosed GBM, but after recurrence, which is typical in the disease, there are no very effective therapies, said Andrew T. Parsa, MD, PhD, a coauthor of the study and chair of Neurological Surgery at Northwestern Memorial Hospital. The study followed patients who received the vaccine after surgery and standard adjuvant therapy.

Figure. Key Statistics for 41 Patients in HSPPC-96 Vaccine Trial

With HSPPC-96, “Survival increased from an average of 33 weeks following progression to about 40 weeks,” said the study’s lead author, Orin Bloch, MD, a neurosurgeon at the hospital, in a press release. He described that result as “a substantial, though not enormous, increase in survival that gives us hope that vaccine therapy, perhaps in combination with other therapies, will increase survival and improve overall care.” In the study, overall survival at 6 months after treatment with HSPPC-96—the primary endpoint—was approximately 90%. After 12 months, nearly 30% of the patients were alive. Additional endpoints included overall survival, progression-free survival (PFS), safety, and immune profiling.

In all, 68 patients with recurrent GBM were screened and underwent surgical resection for the study from October 2007 through October 2011, researchers reported. Nearly 40% of the initial group (27 patients) were excluded postoperatively, including 13 patients from whom the tumor harvested was insufficient to generate the vaccine.

The resulting trial included an intent-to-treat population of 41 patients with a median age of 55 years (21-75 years) who had surgically resectable, recurrent, high-grade GBM. Karnofsky performance scores were >90 for 15 patients (37%), >80 for 20 patients (49%), and >70 for 6 patients (14%). Participants underwent surgery to remove more than 90% of the brain tumor (a gross total resection). The vaccine was then created for each patient using their removed mass, with approximately 7 g of tissue needed to produce a minimum of four 25-mg vaccine doses. The HSPPC-96 vaccine was administered once a week for 4 weeks, then every other week, with a median of 6 doses (range, 1-15 doses). Reasons for discontinuing the vaccine included disease progression (21 patients) and depleted vaccine (13 patients).

After treatment, 90.2% of patients were alive at 6 months (95% CI, 75.9-96.8) and 29.3% were alive at 12 months (95% CI, 16.6-45.7), the authors reported. Median overall survival was 42.6 weeks (95% CI, 34.7-50.5), they wrote. Patients who received a greater number of doses experienced statistically significant better outcomes, with a hazard ratio of 0.85 (95% CI, 0.73-0.99; P = .036) per incremental dosage. There were no treatment-related deaths.

During the trial, there were 37 serious (grade 3—5) adverse events reported. Seventeen could be attributed to the surgical resection, and 1 grade 3 constitutional event was related to the vaccine, the authors reported.

While HSPPC-96 had previously been tested in other tumor types, cancer vaccines work best in patients who have low residual disease, such as brain cancer, Parsa told OncologyLive. He said the HSPPC-96 vaccine was chosen for study because it flows well with treatment for patients who have GBM, with an interval of about two weeks between the tumor’s removal and the vaccine’s administration.

Parsa said that the main goals of the study were to prove the efficacy of the vaccine and prepare for a randomized three-arm trial (NCT01814813), currently under way, that will include about 200 patients. That trial is testing the efficacy of bevacizumab— considered a standard treatment for recurrent GBM—versus the cancer vaccine in tandem with bevacizumab, and is sponsored by the Alliance for Clinical Trials in Oncology, a cooperative group of the NCI.

In addition, an HSPPC-96 vaccine from the Prophage G-100 series that Agenus developed is under study for patients with newly diagnosed GBM in a combination regimen with temozolomide following radiation therapy (NCT00905060).

Forty-six patients have been treated in the phase II study, with a median PFS of 17.8 months, Agenus reported in September. The company is discussing a phase III trial with the FDA.

Reference

1. Bloch O, Crane CA, Fuks Y, et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial [published online December 12, 2013]. Neuro Oncol. 2014;16(2):274-279.