Neuroblastoma (NBL) is the most common solid tumor of childhood outside the central nervous system. About 60% of children with high-risk disease are not cured by current therapy and therefore fundamentally new treatment strategies are necessary. A promising new approach is to engineer the immune system to destroy cancer cells by using chimeric antigen receptors (CAR). CARs can be expressed on certain immune cells and one cell type, Natural Killer T cells (NKTs) are especially suited for immunotherapy of neuroblastoma.
Our group recently showed that NKTs localize to NBL and attack non-malignant cells called tumor-associated macrophages, which provide critical support for the survival and growth of the cancer cells. Our preliminary results show that upon genetic engineering NKTs become capable of targeting neuroblasts themselves in addition to tumor associated macrophages. The most studied NBL associated antigen is GD2. However, this molecule is also expressed on peripheral nerves and although GD2-specific antibody treatment improves survival, it causes severe pain due to peripheral nerve injury. Thus we propose that o-acetyl-GD2, which is only expressed on neuroblastoma cells, is the ideal target and NKTs genetically engineered to express o-acetyl-GD2-specific CAR are safe and destroy neuroblastoma. In the proposed study, we will use in vitro and in vivo experimental systems established in our lab to evaluate the therapeutic potential of oaGD2-CAR NKTs against neuroblastoma. The results will inform the design of a phase I clinical trial and bring a novel, safe and effective therapy for neuroblastoma patients.