Novel combined immunotherapy promising for treatment of malignant brain tumors

A new Phase I clinical trial conducted at Cedars-Sinai Medical Center's Maxine Dunitz Neurosurgical Institute in Los Angeles shows that two innovative treatment approaches may safely be combined to treat patients with highly aggressive, malignant brain tumors called gliomas. The results suggest that combining the two therapies might boost their effectiveness and supports the pursuit of additional studies on this approach to treating these tumors.

In 2009, an estimated 22,070 new cases of primary brain and central nervous system tumors were diagnosed, and nearly 80 percent of these were gliomas, the most prevalent type of malignant brain tumor in adults. Malignant gliomas are tumors that are highly resistant to treatment and usually fatal. Glioblastoma multiforme (GBM) is the most invasive type of glial tumor. These tumors tend to grow rapidly, spread to other tissue, and have a poor prognosis. One of the biggest challenges is that gliomas have roots, or tentacles, making it impossible to completely remove them surgically. Thus a combination of radiation and chemotherapy is the usual course of treatment after surgery.

Researchers investigated the use of dendritic cell vaccination with chemotherapy wafer placement in patients with malignant gliomas. The results of this study, A Phase I Trial of Surgical Resection with Biodegradable Carmustine (BCNU) Wafer Placement Followed by Vaccination with Dendritic Cells Pulsed with Tumor Lysate for Patients with Malignant Gliomas, will be presented by John S. Yu, MD, 4:01 to 4:15 pm, Monday, May 3, 2010, during the 78th Annual Meeting of the American Association of Neurological Surgeons in Philadelphia. Co-authors are Surasak Phuphanich, MD, DSc, Ray M. Chu, MD, Mia Mazer, MS, OPA-C, Hongqiang Wang, PhD, Natalia Serrano, BS, Miriam Nuno, PhD, Jaime Richardson, RN, Christopher J. Wheeler, PhD, Keith L. Black, MD, and Jeremy D. Rudnick, MD.

"Standard chemotherapy is not very effective because drugs are not able to penetrate the blood brain barrier, which prevents most drugs in the bloodstream from entering the brain. In general, current treatments have not yielded significant increases in survival rates, which is why research into novel therapies is so crucial," remarked Dr. Yu.

Biodegradable carmustine (BCNU) is a well-known and frequently used chemotherapy drug that has been utilized since the early 1990s. In biodegradable polymer wafer form, the drug can be delivered to the tumor resection cavity in a controlled-release method over time. This increases the local concentration of BCNU reaching glioma-invaded areas of normal brain, and avoids the concomitant toxicity of systemic drug application.

The individualized dendritic cell vaccine is designed to provide patient-specific and tumor-specific immunotherapy - enabling the immune system to recognize the tumor cells and initiate a cancer-killing response. Dendritic cells are specialized "antigen-presenting cells" that are responsible for identifying immune system targets for the attacking cells of the immune system.

The research team created the dendritic vaccine in the laboratory by combining each patient's own tumor cells with dendritic cells from their blood. This method programs the dendritic cells to identify the glioblastoma cells so the immune system can seek and destroy them.

The researchers explored the theory that immunotherapy may synergize with BCNU wafer chemotherapy by generating both immune and chemo-cytotoxicity without provoking systemic immunosuppression. Thirty-two patients with high grade glioma were enrolled in the study after their tumors were removed and BCNU wafers were placed at the tumor sites. Three dendritic vaccines were administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. The following results were noted:

•Of nine patients for which immunologic data were available, 67 percent demonstrated at least a 1.5-fold increase in immune response, as measured by Interferon-g (IFN-g) response to antigen, compared to 50 percent in previous dendritic cell vaccine trials.

•Most notably, patients with the greatest immune response also experienced the longest survival times. The correlation between the magnitude of the immune response and survival r = 0.72 (P = 0.02) confirmed that immune response may correlate to a clinically meaningful outcome.

•In the recurrent GBM group of 13 patients, median overall survival was 84 weeks (16-351 range).

•For seven newly diagnosed GBM patients, median overall survival was 53 weeks (33-128 range).

•The mean Karnofsky Performance Scale (KPS), a measure of functional impairment, was 90 percent - considered normal.

•The mean mini-mental state examination (MMSE) of 28 remained unchanged throughout the vaccination period. The MMSE measures cognitive impairment and scores above 25 were deemed normal.

•Very few adverse effects occurred. One patient experienced a single grade 3 toxicity of fever/chest pain, and another developed an allergic response requiring hospitalization.

"The preliminary results of this Phase 1 trial indicate that this treatment provides a survival advantage that is favorable compared to other treatments that are often used for recurrent GBMs, and warrants further study," concluded Dr. Yu.