LELAND STANFORD JUNIOR UNIVERSITY, THE
Grant: $777,986 - National Institutes of Health - Sep. 29, 2009
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Award Description: Diffuse intrinsic pontine gliomas are the most deadly and intractable of the pediatric brain tumors with a median overall survival of 9-10 months. Over the last 20 years, there have been numerous clinical trials studying different combinations and timing of radiation and chemotherapies failing to show prolongation of survival. There is a tremendous need for improved therapeutics in this patient population. Part of the difficulty with treating this tumor is a lack of understanding of its basic biology due to the paucity of tumor sample. Because surgery is not part of the treatment paradigm, there is no source of tissue to study. Improved in vitro methods of studying this tumor are needed. EGF receptor variant III (EGFRvIII) is the most common variant of the EGF receptor and is present in many different cancer types but only rarely in normal tissue. The protein is constitutively active and leads directly to a cancer phenotype. This novel peptide sequence is an ideal tumor antigen and is the basis for a peptide vaccine that is one of the most promising agents for the treatment of glioblastoma, the most common malignant brain tumor. Initial phase II studies demonstrate more than a doubling of overall survival when compared to historical controls. Recent work has shown EGFRvIII expression in about 50 percent of pediatric diffuse intrinsic pontine gliomas. These data suggest that EGFRvIII warrants investigation as a target for these deadly pediatric tumors. In our study, we plan to perform a phase I clinical trial evaluating treatment of pediatric patients with diffuse intrinsic pontine glioma using the EGFRvIII peptide vaccine. Patients with newly diagnosed pediatric diffuse intrinsic pontine glioma after conventional radiation therapy will be injected intradermally with the EGFRvIII peptide vaccine along with GM-CSF once a month until disease progression. These patients will be followed with monthly MRI examinations, physical exams, peripheral blood for immunologic analysis, and adverse event monitoring. Our aims will be to establish the safety and tolerability profile of EGFRvIII peptide vaccination in these patients, determine overall survival of patients treated with the vaccine after conventional radiation, and assess humoral and cellular immune responses to explore overall immunogenicity of the vaccine. Moreover, we plan on studying tumor microvesicle secretion into the cerebrospinal fluid of children with diffuse intrinsic pontine gliomas to examine the protein expression and/or alterations in certain genes from these samples that can be used as a diagnostic tool and improve the understanding of this tumor's biology.
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