EPN-28: GM-CSF IS CRITICAL FOR TRASTUZUMAB EFFICACY IN PEDIATRIC EPENDYMOMA

A number of studies have demonstrated correlation of host immune factors with outcome in ependymoma (EPN). This supports the development of immunotherapy for EPN, a tumor in which approximately 50% of patients suffer recurrence and for which chemotherapy has not yet shown any benefit. Mechanisms of therapeutic antibody effect in cancer treatment have been shown to include recruitment of host anti-tumor immunity. In a transcriptomic screen of FDA-approved therapeutic antibody targets we identified ERBB2, targetable by therapeutic antibody trastuzumab, as overexpressed in all subgroups of EPN, which was subsequently confirmed by protein analysis. In a series of preclinical studies we evaluated the combination of therapeutic antibody trastuzumab with immunostimulatory factors GM-CSF and IL2 for the treatment of EPN. Novel EPN 1q+ cell lines 811 and 928 were co-cultured with autologous peripheral blood immune cells to measure immune-cell mediated cytotoxicity using live cell imaging. This demonstrated that antibody-dependent cell-mediated cytotoxity (ADCC) is dependent on addition of GM-CSF to trastuzumab treatment. This implicates monocyte/macrophages as effectors of trastuzumab-dependent anti-tumor effect in EPN. Primary human EPN organotype culture studies demonstrated decreased tumor proliferation and increased immune cell proliferation in response to combined trastuzumab, GM-CSF and IL2. As the first stage in a clinical trial of trastuzumab in recurrent EPN we have recruited patients to a pilot study of GM-CSF delivered prior to surgery. Post-treatment tumor samples demonstrated upregulated antigen processing and presentation genes, a hallmark of GM-CSF activated macrophage/monocyte immunophenotype. These results demonstrate the importance of combining GM-CSF with trastuzumab in EPN.