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Combining dendritic cell vaccination with imiquimod for the treatment of glioblastoma more than doubled survival in a small intervention group during a phase I trial.
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 conventionally treated patients at the University of California, Los Angeles, survived to 2 years, and only 20% survived to 3 years.
Median progression-free survival and median overall survival in the vaccinated group were 18 months and 34 months, respectively. This compared with 7 months and 15 months, respectively, for patients in 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.
The vaccines consisted of autologous dendritic cells pulsed with lysates from GBM tumor cells. 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.
The control group consisted of 191 patients with GBM at UCLA, who received standard treatment. The average age 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 (Calif.) University, who reviewed the poster.
Nearly all patients had de novo infiltration of T lymphocytes into CNS tumors. In addition, CNS tumors were found to express known tumor-associated antigens. Five patients also had an increase in tumor antigen-specific CD8-positive T cells following vaccination.
The relationship between response and patient survival was disappointing though. "In my opinion, there was not a strong correlation between the response to these defined tumor antigens and patient response," Dr. Wong said.
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.
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.
Liau L.M. et al. Dendritic cell vaccination in combination with TLR-7 agonist, imiquimod, following radio-chemotherapy for newly diagnosed glioblastoma. Abstract 2021.
Commentary |
In this report of a phase I study, tumor lysate-pulsed dendritic cell therapy plus topical imiquimod, a TLR-7 agonist, was nontoxic and generated specific immunologic responses in brain tumor patients. In combination with the abstract by Sampson et al., this study makes clear that vaccine strategies represent a potential therapeutic approach for patients with malignant brain tumors. Hopefully, further studies of vaccine strategies in combination with chemotherapy agents such as temozolomide as well as radiotherapy will demonstrate a role for a vaccine. Many issues still need to be resolved, however, including the optimal antigen to target, the presentation of this antigen (i.e. either using it with or without dendritic cell presentation), and the timing of vaccine strategies relative to surgery, radiation, and chemotherapy. Presumably, vaccine strategies will be most effective at a time of minimal residual disease, i.e., in patients whose MRIs show no obvious gross residual tumor after initial intervention. There is less likelihood of results in patients with bulky disease. — Henry S. Friedman, M.D.
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