Neuroblastoma is the most common extracranial solid tumor seen in children, and expresses the disialoganglioside GD2 on its surface. For patients who have high risk disease or whose disease recurs after completing therapy, there are limited options. Allogeneic hematopoietic stem cell transplant (AlloHSCT) is a transfusion of hematopoietic stem cells from a healthy donor to a patient who has been treated with high doses of chemotherapy and/or radiation, and is typically used clinically for children with leukemia or lymphoma. But alloHSCT has had limited success thus far in attacking neuroblastoma with a graft-versus-tumor (GVT) effect, and has introduced lethal graft-versus-host-disease (GVHD). The long term objective of this proposal is to enhance the GVT effect against neuroblastoma. This proposal explores 3 specific aims to improve GVT effects using animal models of alloHSCT. First we will explore usage of an immunocytokine called hu14.18-IL2, a humanized GD2 monoclonal antibody linked to interleukin (IL)-2, to enhance the GVT effect, improving the efficacy of the transplant. This antibody has already been given to children with neuroblastoma in clinical trials but is not curative, and has not been tested in the alloHSCT setting. Second, we will activate allogeneic natural killer (NK) cells with IL-15 and CD137L-expressing artificial antigen presenting cells, and infuse them for the first time with hu14.18-IL2 as a combination strategy for improving GVT further. We will control any potential GVHD by inhibiting the JAK/STAT pathway and blocking tumor necrosis factor-alpha production. Lastly, we will label NK cells with a nonradioactive isotope of fluorine (?F) that will make these cells detectable by MRI, determine how ?F-labeled NK cells traffic to neuroblastoma tumors after alloHSCT and if hu14.18-IL2 can further attract NK cells to the tumor. The ultimate goal is to support the research priorities of the National Cancer Institute by developing research that will lead to novel therapies for neuroblastoma. Success of any of the individual aims will be a major advance in making alloHSCT more effective for neuroblastoma. Successful translation of the entire proposal will lead to an innovative combination immunotherapy platform for treating neuroblastoma.
Neuroblastoma is the most common extracranial solid tumor seen in children, but has not yet been successfully managed with stem cell transplants from healthy allogeneic donors, called the graft-versus-tumor (GVT) effect. This proposal offers 3 exciting options to improve GVT effects: usage of an antibody that targets neuroblastoma and activates the immune system, infusion of natural killer (NK) cells grown and activated in culture that can attach to the antibody and eliminate the tumor, and labeling of the NK cells with a nonradioactive isotope of fluorine to allow detection by MRI. Success of any of these aims will be a step forward in improving GVT effects for neuroblastoma, and because all 3 options are clinically available, could be rapidly translated to patients with neuroblastoma.
