RNA-Based Immunotherapy Targeting Antigens Unique to Brain Tumor Stem Cells

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DESCRIPTION (provided by applicant): NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications A subset of cells in glioblastoma multiforme (GBM) have been identified that enjoy a unique capacity to regenerate tumors. These brain tumor stem cells (BTSC) have been segregated by the neural stem cell marker, CD133, and are widely believed to be the cells responsible for resistance to conventional therapies. An effective means of specifically eliminating these cells may reduce the need for intensive and non-specific conventional therapy and lower the risk of tumor recurrence. In our original proposal, we offered vaccines consisting of dendritic cells (DCs) loaded with amplified total tumor RNA derived from BTSCs as an innovative strategy to induce cellular and humoral antitumor immune responses against these BTSCs. Recently, temozolomide (TMZ), a myelosuppressive chemotherapy, has shown a survival benefit in patients with GBM. Unfortunately, the lymphopenia induced by TMZ would be predicted to curtail the induction of productive antitumor immune responses by such vaccines. However, following periods of lymphopenia, such as those induced by TMZ, there is a homeostatic proliferation of the host's remaining lymphocytes, which enjoy a lowered threshold for activation. As a result, anti-tumor lymphocytes that encounter their cognate antigen during this recovery phase, perhaps in the form of a vaccine, may have a competitive advantage and become over-represented in the recovering lymphocyte population. Our preliminary data demonstrate that peptide vaccines targeting a tumor-specific antigen, when given during the recovery from TMZ-induced lymphopenia, produced dramatically enhanced humoral responses and increased antigen-specific T-cell frequencies in mice and humans. Furthermore, increasing the dose of TMZ or treating with serial cycles of TMZ generated progressively higher T-cell frequencies in response to vaccination. These results highlight vaccination during hematopoietic recovery from serial TMZ as a novel strategy for enhancing antitumor immunity that needs to be investigated in the context of vaccines targeting BTSCs. Our Competitive Supplement would propose then to investigate the effects of TMZ on the efficacy of vaccines consisting of DCs loaded with TTRNA derived from BTSCs. Consistent with the goals of the American Recovery and Reinvestment Act, this Supplement would accelerate the tempo of our research in this area and allow for job creation and retention. PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page PUBLIC HEALTH RELEVANCE: Treatment for malignant primary brain tumors, which are the most common cause of death among children and account for more deaths in adults than melanoma, currently represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States. A subset of malignant primary brain tumor cells (BTSCs), called brain tumor stem cells, enjoy a unique capacity to regenerate tumors and to resist conventional therapies. In this proposal we will see if targeting antigens preferentially or uniquely expressed by BTSCs in the context of chemotherapy-induced myelosuppression will enhance the efficacy of immunotherapy without inducing autoimmunity. PHS 398/2590 (Rev. 11/07) Page 1 Continuation Format Page