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Targeting Tumor-Associated Macrophages to Improve Immunotherapy in Neuroblastoma

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Pediatric Cancer

Shweta Joshi (Rady)

Judith Varner (MCC)

Neuroblastoma is a cancer that accounts for more than 15% of all childhood cancer deaths. Despite multimodal therapy, the 5-year survival rate of children with high-risk disease is very low. Hence, novel, and safe therapies are needed to combat this childhood cancer. Here, we propose a targeted strategy to improve the effectiveness of anti-cancer therapy for this childhood cancer. In studies performed in the laboratory, we found that two enzymes, Syk and PI3K gamma, each controls the tumor-promoting properties of immune cells called macrophages. When cancer cells start to develop in the body, macrophages are quickly recruited into the tumor to kill and destroy cancer cells. However, these macrophages are very quickly re-educated by cancer cells to promote tumor growth and suppress the activity of other immune cells, especially tumor-killing T cells. This change in macrophages prevents killer T cell entry into tumors and suppresses the efficacy of current therapy. Our studies have shown that inhibiting the action of Syk or PI3K gamma causes macrophages and T cells to mount a continued response against various experimental solid tumors. Indeed, early clinical studies of the inhibitor eganelisib in adult cancer patients demonstrated improved clinical responses to the standard of care therapy. Hence, we propose that Syk inhibitors or/and PI3K gamma inhibitors together with anti-GD2 immunotherapy have the potential to improve the survival of pediatric cancer patients with neuroblastoma. The results of our proposed preclinical studies may be rapidly translated into therapy against neuroblastoma to improve the survival of children with high-risk disease.

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