CHICAGO — Combining dendritic cell vaccination with imiquimod for the treatment of glioblastoma more than doubled survival in an intervention group compared to a conventionally treated control group in a small phase I trial presented as a poster at the annual meeting of the American Society of Clinical Oncology.
Two-year survival—the primary clinical end point—for 19 patients treated with the dendritic cell vaccines was 68%, and 3-year survival was 43%. In comparison, only 26% of control patients at the University of California, Los Angeles, survived to 2 years, and only 20% survived to 3 years.
To date, the median progression-free survival and median overall survival in the vaccinated group are 18 months and 34 months, respectively. This compared with 7 months and 15 months, respectively, for control patients from the published literature.
Dr. Linda Liau, a neurosurgeon at UCLA, and her colleagues presented immunologic response data for 13 patients with newly diagnosed glioblastoma multiforme (GBM). Patients underwent resection, followed by a 6-week course of radiation and chemotherapy with temozolomide. Two weeks prior to the first immunization, patients underwent MRI. One week before the first immunization, patients underwent leukapheresis and immunologic assays.
The vaccines were composed of autologous dendritic cells that have been pulsed with lysates from GBM tumor cells. Preclinical studies have demonstrated that dendritic cells are preferentially responsible for the sensitization of naive T cells in their first exposure to antigen.
Each patient initially received three vaccinations at 2-week intervals. Four patients received 1 million dendritic cells per immunization; four others received 5 million dendritic cells per immunization, and the remaining five received 10 million dendritic cells per immunization.
Patients without tumor progression subsequently received booster injections every 3 months combined with topical administration of imiquimod, which is a toll-like receptor-7 agonist that enhances both the innate and acquired immune response. Imiquimod (Aldara) is indicated for the treatment of actinic keratosis, superficial basal cell carcinoma, and external genital and perianal warts.
Immunologic responses to tumor antigens were monitored using several methods. Clinical tumor growth was monitored by MRI every 2 months.
The control group consisted of a total of 191 patients with GBM at UCLA, who received standard treatment. The average age of the patients in the vaccinated and control groups was 51 and 49 years, respectively.
“It appears that vaccination approaches in general are very successful,” said Dr. Albert Wong of Stanford University Palo Alto, Calif., who reviewed the poster during a discussion session.
Almost all of the patients had de novo infiltration of T lymphocytes into CNS tumors. In addition, CNS tumors were found to be expressing known tumor-associated antigens. Five patients also had an increase in tumor antigen-specific CD8-positive T cells with vaccination.
The relationship between response to tumor antigens and patient survival was somewhat disappointing. “In my opinion, there was not a strong correlation between the response to these defined tumor antigens and patient response,” Dr. Wong said.
In general there is a need for better surrogate markers to assess immune response. Perhaps the best may be the infiltration of T cells into the tumor, he added.
In terms of safety, no grade 3 or 4 adverse events were reported. The most frequent adverse events were low-grade fever, injection-site itching and pain, and arthralgia and myalgia. Seizures also occurred that were possibly related to the vaccines; however, seizures are also typical in GBM patients.
An important next step is to identify what the true tumor antigens are, in order to better refine the vaccine. Dr. Wong likened the current generation of dendritic cell vaccines to using foxglove to treat “x,” when it would really be better to extract and use the active component, digitalis.
Dr. Liau did not disclose any conflicts of interest. The study was sponsored in part by Northwest Biotherapeutics Inc., which is developing the technology behind the vaccines. A phase II clinical trial, sponsored by Northwest Biotherapeutics Inc., is underway.