Peptide-Based Vaccine Therapy for Childhood Malignant Gliomas

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DESCRIPTION (provided by applicant): Malignant astrocytomas are among the most common and deadly brain tumors of childhood. Most children with brainstem and subtotally resected non-brainstem malignant gliomas die within several years of diagnosis, despite current treatments. Accordingly, new treatment approaches are needed that target the unique features of these tumors. During the last decade, we have gained significant preclinical and clinical experience with immunotherapy for adult gliomas, and propose to extend these insights to the treatment of childhood malignant gliomas, based on our observation of substantial similarities between these tumors in their expression of glioma-associated antigens (GAAs). Building upon these data, we propose the use of a GAA- based vaccine cocktail, combined with an immunoadjuvant (poly-ICLC), for children with newly diagnosed malignant brainstem gliomas (Stratum 1) and subtotally resected non-brainstem malignant gliomas (Stratum 2). Participants will be treated with s.c. injections of GAA vaccines every 3 weeks for 8 courses and poly-ICLC will be administered (30 <g/kg i.m.) on the day of each vaccination. Participants will be evaluated for adverse events, regimen limiting toxicity (RLT), and treatment response by clinical and laboratory evaluations and MR imaging. Participants who demonstrate disease stabilization or regression without RLT may undergo additional vaccinations. These studies take advantage of unique institutional resources provided by our Immunological Monitoring and Cellular Products Laboratory, which are integrated into the clinical trial design. We hypothesize that vaccine-based immunotherapy will not only prove safe for the treatment of pediatric malignant gliomas, but will also demonstrate activity as assessed by clinical, radiologic, and immunologic parameters. To address our hypotheses, we propose studies with the following specific aims: 1) To assess safety of vaccination using multiple glioma-associated antigen peptides and immunoadjuvant therapy in children with newly diagnosed brainstem and subtotally resected non-brainstem high-grade gliomas; and 2) To determine the rate and magnitude of immune response in post-vaccine peripheral blood mononuclear cells against GAA peptides, in response to peptide-based vaccine therapy, using IFN-3-enzyme-linked immuno-spot (ELISPOT) and tetramer assays. We will treat a total of 12 patients in each of the two strata. Preliminary data regarding clinical and imaging responses to therapy will also be obtained. The results from this study will allow us to determine whether a subsequent larger, phase II trial is warranted for either or both strata. PUBLIC HEALTH RELEVANCE: Our clinical study and biological correlative analyses will represent the first application of a multipeptide epitope vaccine-based strategy to a pediatric glioma cohort, providing fundamental data for assessing safety, and clinical and immunological efficacy, of immunotherapeutic strategies in the pediatric brain tumor context.