High-risk neuroblastoma (NB) is a lethal childhood malignancy treated with an antibody called dinutuximab. Dinutuximab binds to a molecule found on neuroblastoma cells called GD2 and results in killing the tumor cells. About 1/2 of NB patients will relapse after initial therapy, and relapse is often treated with cancer chemotherapy drugs temozolomide (TMZ) + irinotecan (IRN) + dinutuximab. We have shown that dinutuximab can enhance the killing of NB tumors grown in special mice (i.e. patient-derived xenografts =PDXs) to TMZ + IRN. We will show that dinutuximab enhances activity of TMZ + IRN against tumors with high binding of dinutuximab (high GD2) but not those with low dinutuximab binding ...
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High-risk neuroblastoma (NB) is a lethal childhood malignancy treated with an antibody called dinutuximab. Dinutuximab binds to a molecule found on neuroblastoma cells called GD2 and results in killing the tumor cells. About 1/2 of NB patients will relapse after initial therapy, and relapse is often treated with cancer chemotherapy drugs temozolomide (TMZ) + irinotecan (IRN) + dinutuximab. We have shown that dinutuximab can enhance the killing of NB tumors grown in special mice (i.e. patient-derived xenografts =PDXs) to TMZ + IRN. We will show that dinutuximab enhances activity of TMZ + IRN against tumors with high binding of dinutuximab (high GD2) but not those with low dinutuximab binding to tumor cells. To characterize mechanism(s) of low dinutuximab binding we will compare low and high-GD2 cell lines and PDXs for expression of genes and proteins involved in making or breaking down GD2. Using gene knockdown and/or forced expression of key genes we will create pairs of low/high GD2 expressing cell lines and we will use those to assess response in xenografts to TMZ + IRN +/- dinutuximab. We will develop a multi-color antibody binding assay that will allow us to measure the % positive and intensity of dinutuximab binding to tumor cells from patients with recurrent NB. In collaboration with the Children’s Oncology Group (COG) we will employ this assay to test dinutuximab binding to tumor cell from patients on clinical trials. We will determine the association of clinical response to the density of dinutuximab binding and % of NB cells with positive dinutuximab staining. This project will provide a comprehensive set of non-clinical and clinical data that will determine if measuring anti-GD2 binding in recurrent neuroblastoma can identify patients not likely to respond to chemoimmunotherapy. We will also determine if antibodies that bind to tumor cells via molecules other than GD2 can enhance chemoimmunotherapy in our PDX preclinical models.
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