LOS ANGELES, CA. - Scientists at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute have found that a dendritic cell "vaccine" was able to elicit a systemic immune response while directing tumor-fighting T-cells to the site of a brain tumor. The treatment resulted in extended lengths of survival for patients suffering from highly aggressive, malignant brain tumors called glioblastoma multiforme (GBM or glioma).
Results of the Phase I study are published in the Feb. 1 issue of the journal Cancer Research, and a larger Phase II study is currently underway.
"Although this first study was conducted with a small number of patients, the results greatly exceeded our expectations," said Keith L. Black, M.D., director of the Institute and the study's lead investigator. "Malignant gliomas are very deadly tumors. Even with aggressive therapy, including surgical resection followed by radiation therapy and chemotherapy, the median length of survival is less than one year. But the median survival for patients who were given the dendritic cell vaccine was extended significantly."
In fact, according to the paper, median length of survival for patients in the study was 455 days, compared with 257 days for the control group that consisted of patients with similar characteristics related to age, gender, tumor removal and treatment. The control group was made up of patients who either were treated at Cedars-Sinai within a two-year period before the vaccine became available or were treated at the hospital while the study was taking place but chose not to participate. The same surgeons were involved with both groups of patients.
"Obviously, we cannot offer a cure for these devastating cancers at this point, but the results of this early study are very encouraging," said Dr. Black. "We see evidence that we are moving in the right direction, and additional studies will be conducted to target the tumor cells even more effectively. This is only a start but it is a promising start with visible results."
Viewers of recent episodes of NBC-TV's drama "ER" may recognize dendritic cell immunotherapy as one of the treatment options considered to combat Dr. Mark Greene's brain tumor. Although this therapy is in its infancy, Dr. Black, a consultant to the show, believes this story line may help portray the hope that this real therapy is beginning to offer.
Unlike a typical vaccine that is used to prevent an illness, this type of vaccine is intended to prevent the recurrence of a specific cancer. Gliomas are extremely aggressive and deadly, in part because they elude detection by the immune system and grow unhindered.
In a sense, the vaccine brings the tumor cells to the attention of the immune system and enables it to attack them with disease-fighting T-cells. Dendritic cells circulate in the bloodstream and are also known as antigen-presenting cells because of their role in identifying foreign invaders for the immune system.
To create the vaccine, researchers took glioma cells from a tumor that had been surgically removed. In a complex and highly controlled sequence of events, they cultured these cells in the lab, then combined and cultured several glioma cells with dendritic cells taken from blood drawn from a vein.
Patients in the study were given three vaccinations under the skin at two-week intervals. Systemic T-cell activity was evaluated through blood work that was performed one week after each vaccination, and six and 12 weeks after the last vaccination. Of seven patients evaluated, four demonstrated enhanced cytotoxic T-cell activity after vaccination. This cytotoxicity (cancer-cell killing capability) was sustained through the last lab work, three months after the final vaccination.
T-cell activity at the site of the tumor was evaluated in four patients who underwent subsequent surgical procedures because magnetic resonance imaging suggested that the tumors were growing again, despite surgical removal. Two of the four patients had significant T-cell infiltration into areas of tumor. This T-cell activity was not seen on tumor specimens obtained before vaccination.
In the other two patients, few immune system cells were seen in surgical specimens taken before and after vaccination, and both of these patients died from tumor progression. However, all four patients who underwent a second operation had either pre-existing or new systemic cytotoxicity, and a future challenge will be to find a way to identify which patients will respond well to systemic cytotoxicity.
Although clinical trials using dendritic cell immunotherapy have been performed on four other cancers - lymphoma, melanoma, prostate cancer and renal cell carcinoma - this Phase I study is believed to be the first on glioma cells. It showed that the vaccinations were well tolerated, causing only mild side effects in a few patients. A larger Phase II study is underway to confirm that this immunotherapy strategy can induce an anti-tumor response and increase survival in patients with these catastrophic tumors.
The study was supported entirely by the Cedars-Sinai Maxine Dunitz Neurosurgical Institute.
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