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Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL

The purpose of this study was to provide the first pre-clinical evidence for antibody targeting of anaplastic lymphoma kinase (ALK) in human neuroblastoma. ALK is a receptor tyrosine kinase expressed by the majority of neuroblastoma tumors. Germline mutations of ALK, shown to account for most cases of familial neuroblastoma, as well as somatically acquired ALK aberrations, induce increased auto-phosphorylation and constitutive ALK activation and increased downstream signaling. Antibody targeting of receptor tyrosine kinases, as monotherapy or together with small-molecule inhibitors, is highly effective in other cancers such as breast and lung cancer. While antibody-mediated immunotherapy targeting of disialoganglioside GD2 has recently been reported to significantly increase 2-year survival in high-risk neuroblastoma patients, over half the patients receiving this therapy ultimately succumb to their disease and therapeutic alternatives are urgently needed to improve survival rates of this devastating pediatric cancer. Therefore, we hypothesized that antibody targeting of ALK in neuroblastoma was a therapeutically appropriate strategy. To first confirm the potential of anti-ALK antibody-mediated immunotherapy, we used in vitro assays to demonstrate enhanced immune-cell induced cytotoxicity of antibody-treated human neuroblastoma-derived cell lines. We next showed that in vitro antibody treatment of neuroblastoma cell lines expressing activated ALK led to growth inhibition and cell death. These effects were enhanced by treatment with PF-02341066, an orally available small-molecule inhibitor of the ALK tyrosine kinase. To identify the mechanism behind this enhanced combined effect, we used flow cytometry to show that PF-02341066 sensitizes cells to antibody treatment by inducing accumulation of cell-surface ALK, thus increasing the accessibility of antigen for antibody binding. Finally, to further predict in vivo cytotoxic mechanisms of dual ALK targeting, we used flow cytometry to demonstrate enhanced apoptosis and proliferation inhibition resulting from combined antibody and inhibitor treatment as compared to either drug alone. Taken together, these findings provide strong evidence for the therapeutic relevance of antibody targeting of ALK in neuroblastoma and argue for the rapid development and further testing of a clinical grade anti-ALK antibody.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4563. doi:10.1158/1538-7445.AM2011-4563