B7-h3-specific engager T cells for the immunotherapy of pediatric solid tumors
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KeywordsOsteosarcoma Neuroblastoma High Grade Glioma Effector Function Internal Ribosomal Entry Site
B7-H3 positive tumors, including osteosarcoma, neuroblastoma, and high grade glioma, cause significant morbidity and mortality despite aggressive multimodality treatments. Current B7-H3-targeted immune-therapies take advantage of the monoclonal antibody 8H9, which is actively being evaluated in Phase I clinical trials. Engager T cells, which secrete bispecific engager molecules consisting of single chain variable fragments specific for CD3 and a tumor antigen, are a new class of antigen-specific T cells, with the unique ability to redirect bystander T cells to tumors, amplifying anti-tumor effects. The goal of this project was to develop B7-H3-specific Engager T cells, and pre-clinically evaluate their effector function in vitro and in vivo.
B7-H3-Engager T cells were generated by transducing T cells with a retroviral vector encoding a B7-H3-specific T cell engager and mOrange separated by an internal ribosomal entry site. B7-H3-Engager T cell effector function was then evaluated in vitro and in a metastatic osteosarcoma xenograft model.
We successfully generated B7-H3-Engager T cells and demonstrate that these cells recognize and kill B7-H3-positive tumor cells in an antigen-dependent manner, and have potent anti-osteosarcoma activity in vivo. Thus, B7-H3-Engager T cells may present a promising alternative to current T cell immunotherapy approaches for pediatric solid tumors.
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