MB-01: RADIATION AS AN IMMUNOLOGICAL ADJUVANT IN GROUP 3 AND 4 MEDULLOBLASTOMA CELLS

Medulloblastoma is the most common malignant brain tumor in children. Recent advances in gene expression profiling have provided evidence of four distinct medulloblastoma molecular subgroups (Wnt, Shh, group 3, and group 4), associated with remarkably different prognoses. Tumors of group 3 (MYC amplification) and group 4 (isochromosome 17q) exhibit large cell/anaplastic and classic histology and offer the lowest patient survival rate. Immunotherapy, specifically designed to target these poorly-performing subgroups, may offer therapeutic improvement. Although monoclonal antibody (mAb) therapy has not yet been shown to be effective for the treatment of brain tumors, recent data indicate that radiation therapy can induce immunogenic modulation characterized by cell-surface phenotypic changes, leading to augmented tumor cell/cytotoxic T-cell interaction. We examined the ability of radiation to upregulate mAb therapy targets in medulloblastoma. Our data showed that low dose X-ray radiation significantly increased cell-surface and total protein expression of mAb targets CD137 (a member of the TNF receptor superfamily), Major Histocompatability Complex class I, and intercellular adhesion molecule-1 in medulloblastoma cells in vitro. Upregulation of these molecules could significantly influence the outcome of T cell-tumor cell interaction and enhance T cell mediated cell death. Low dose radiation also increased cell-surface expression of mAb target molecules (Her-2, FGF, and VEGF). Upregulation of these cell surface molecules is associated with phosphorylation of NF-κB. We demonstrate that the novel combination of radiation and antibody therapy can achieve a synergistic therapeutic effect. This finding offers a new therapeutic combination for medulloblastoma and expands the population eligible for targeted therapy.