Malignant brain tumors now represent the most frequent cause of cancer death in children. Despite aggressive and highly toxic multi-modality therapy including surgery, radiation therapy, and high-dose chemotherapy coupled with peripheral blood stem cell transplantation, almost half the children diagnosed with the most common malignant brain tumors will still die from recurrent disease. Furthermore, survivors are often left with severe and lifelong treatment-associated deficits that hinder their learning capacity and motor functions. The development of more effective and specific therapies that will not add further toxicity to existing treatments is critical in improving clinical outcomes for children affected by malignant brain tumors. Immunotherapy targeting malignant brain tumors is a promising treatment strategy that may meet this clear and urgent need.

Despite considerable advancements and promising clinical results observed in immunotherapy trials at our center and others directed against adult malignant brain tumors, efforts in the immunologic treatment of pediatric brain tumors have been relatively limited. This is due, at least in part, to the fact that tumor tissue available for cancer vaccine preparation is often limited in pediatric brain cancers, making the design of cancer vaccines difficult in this population.

We have used pioneering techniques developed at our institution for making suitable cancer vaccines from as few as 100 tumor cells, making possible the ability to offer cancer immunotherapy to the majority of patients from which small amounts of tumor tissue can be obtained during surgery or biopsy. This approach uses the most effective immune cells of the body, called dendritic cells, or DCs, in an attempt to activate the immune system to recognize the difference between normal brain tissue and the malignant brain tumor cells and lead to the specific killing of altered tumor cells. After activating immune cells harvested from the blood of patients with recurrent brain tumors (medulloblastomas and primitive neuroectodermal tumors or PNETs) with their own dendritic cells, we grow these activated immune cells to large numbers in a clinical laboratory and return them to the patient after they have completed chemotherapy. By returning these cells to the patient after chemotherapy, we hope to take advantage of the body's own attempt to recover normal white blood cell counts to help these tumor-specific immune cells grow to even larger numbers inside the patient. We will also attempt to "boost" the response of these cells using continued vaccination with the dendritic cells that we harvested from the patient previously. This type of complex immunotherapy treatment is called adoptive cellular therapy and has shown significant promise in the treatment of other cancers.

This study will have two phases. During Phase I, we will treat patients with increasing doses of the tumor-specific immune cells that we have expanded in our clinical laboratory to establish the safety of this treatment regimen. These patients will also receive dendritic cell vaccines to help boost the function of these immune cells and maintain their growth after being returned to the patient. We expect to treat approximately nine patients during the Phase I component to establish that this treatment seems safe. In the Phase II component, once the treatment has been shown to be safe, we will treat a larger number of patients (approximately 35) with expanded tumor-specific immune cells and dendritic cell vaccines and evaluate the impact on tumor growth in these patients. This will allow us to determine whether tumor growth is prevented or delayed compared to patients that have received similar treatment without immunotherapy. This type of comparison to previously treated patients (called historical control comparison) will allow us to determine whether this treatment regimen looks promising enough to evaluate in larger clinical trials to definitively establish the effectiveness of this approach.

Immunotherapy is a specific approach to treating cancer that has shown promise in adult patients for the treatment of melanoma, malignant brain tumors, and other cancers, and we hope to use the experience we have gained in the immunologic treatment of adult patients with malignant brain tumors at our center to improve the clinical outcome for children affected by this disease. This study has significant potential to impact the families of civilians and military dependents, as the brain is the most frequent site of crippling injuries in humans and, unfortunately, brain cancer is currently the leading cause of cancer deaths in children in the United States.