The purpose of this project is to advance promising cell based and gene based immunotherapy of malignant gliomas from preliminary animal studies to phase I/II clinical trials. We have shown that glioma tumor antigen presentation through subcutaneous vaccination with autologous dendritic cells primed against autologous major histocompatibility complex type I (MHC-I)-associated tumor peptides induces a potent anti-tumor immune response in a murine glioma model. We previously demonstrated that vaccination with tumor cells engineered to secrete granulocyte/macrophage-colony stimulating factor (GM-CSF) elicits a cytotoxic T-cell mediated immune response in murine intracranial glioma and metastasis models. We have implemented these preclinical studies into clinical protocols for patients with glioblastoma multiforme and anaplastic astrocytoma. We are completing a preliminary phase I trial based on a dendritic cell therapeutic strategy. Preliminary results demonstrate that this form of dendritic cell vaccination can induce a cytotoxic T-cell response which targets intracranial tumor cells. Three hypotheses are proposed for investigation: 1) Induction of peripheral antigen presentation will generate tumor specific T-cells. 2) Cytotoxic T-cells will migrate to and kill intracranial glioma cells. 3) Peripheral vaccination will induce clinical responses and extend survival in patients with glioblastoma and anaplastic astrocytoma. Based on our hypotheses, we will carry out two phase I studies of peripheral vaccination against glioma, the first using an alternative form of dendritic cell immunotherapy with an escalated dose of dendritic cells primed with tumor lysate derived peptides. Concurrently, we will initiate a phase I protocol using a vaccine consisting of allogeneic glioma cells mixed with fibroblasts engineered to secrete GM-CSF. In these studies, we propose the following specific aims: 1) to monitor patients for cellular immune responses and 2) to evaluate the safety and the efficacy of these immunologic strategies. A phase II trial will be initiated in year 3 of the training grant based on the phase I studies.
