Primary medulloblastomas express functional CD1d and can be targeted for immunotherapy with NKT cells (156.25)

Abstract Medulloblastoma (MB) is the most common brain tumor of childhood. Current therapies are not curable for a third of patients and have debilitating long-term toxicity. In the initial screen of potential targets for immunotherapy, we performed gene expression analysis of twenty primary MB tumors and found that nine of them expressed high levels of CD1d RNA. Nearly all tumors cells in the corresponding specimens expressed CD1d protein on the cell surface. Two of five analyzed MB cell lines (DAOY and MHH-MED-8A) also were CD1d-positive. Functional experiments demonstrated that both cell lines effectively presented αGalactosylceramide (αGalCer) to activate NKT-cell cytokine production, proliferation, and cytotoxicity. The effector to target ratio as low as 2:1 was sufficient to kill nearly 100% of MB cells in vitro. The cytotoxicity was CD1d-restricted as it was inhibited by anti-CD1d blocking mAb. A single intracranial injection of 2X106 ex-vivo expanded human NKT cells and αGalCer in NOD/SCID/β2m mice with 6-day established xenografts of luciferase-transduced DAOY cells resulted in rapid tumor regression with 30% cure rate. The therapy was well-tolerated. Therefore, CD1d-positive MB could be targeted for immunotherapy with NKTs that has a curative potential.