Neuroblastoma remains a serious childhood malignancy, accounting for 8-10% of all childhood cancers. Prognosis for patients with advanced disease remains poor, with a 2-year disease-free survival of only 10-30%. Recent clinical research has shown that for patients with advanced disease, bone marrow transplantation (BMT) with purged autologous marrow improves event-free survival. However, the majority of patients still relapse within 2 years after transplant. Immune intervention early after transplant might improve survival of these patients. Our preliminary data in an experimental model indicates that T cells capable of responding to a neuroblastoma tumor vaccine are required for induction of anti-tumor immunity after BMT. Immune regulatory T cells (CD4+CD25+) have been found to play a key role in regulating self-non-self recognition by the immune system, and it appears that these cells can be recruited or induced by tumors to prevent immune activation and tumor elimination. The presence of these regulatory cells in the diseased host may in part explain the low degree of success with tumor vaccines. The time period early after BMT, before regulatory T cells have reestablished dominant peripheral tolerance, offers a unique setting to induce effective anti-tumor immunity by combining T cell add-back and tumor vaccination with the inhibition of CD4+25+ T cell-mediated tolerance. Utilizing a mouse model for neuroblastoma, Neuro-2a, we hypothesize that: (1) Using a novel technology, nucleofection, neuroblastoma can be genetically engineered with DNA plasmid vectors to rapidly and efficiently express costimulatory/accessory molecules (CDS0, CD86, ICAM-1, and/or 4-1BBL), and that these engineered cells can serve as a potent tumor vaccine; (2) CD25+ cells suppress anti-neuroblastoma immunity, and depletion of these regulatory T cells augments immunity during tumor vaccination by increasing the contribution of multiple immune effector populations; and (3) Optimal T cell immunity to neuroblastoma can be induced early post-BMT by combining T cell addback with novel tumor vaccines in a setting where cellular mediators of tolerance induction (to tumor) have been removed. The goal of these studies is to provide preclinical data that will lead to the testing of novel immunotherapeutic strategies to prevent neuroblastoma relapse after BMT. ? ?
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