Natural Killer T cells with an IL-15-armored GD2-specific CAR for Children with Neuroblastoma
Background
The overall goal of this proposal is to develop and clinically test a conceptually new form of cancer immunotherapy for children with neuroblastoma (NB) using native and engineered properties of Natural Killer T cells (NKTs). We found that NKTs target tumor-associated macrophages (TAMs) inside neuroblastoma tumors, thereby removing an essential support for tumor cells. To render NKTs directly cytotoxic against NB cells, we engineered them to express a chimeric antigen receptor (CAR) specific for the GD2 ganglioside (CAR.GD2), which has been targeted with T cells in NB patients in clinical trials that produced promising results. To ensure that CAR NKTs can last longer in patients, we added interleukin-15, a molecule that can help NKT cells expand and survive.
Project Goals
We hypothesize that CAR.GD2 NKTs will be safe and have antitumor efficacy in NB via targeting of neuroblast-supportive TAMs and neuroblasts themselves. The following specific aims will test our hypothesis: 1) we’ll evaluate the safety of ex vivo expanded CAR.GD2 NKTs in patients with resistant/recurrent NB; and, 2) monitor the in vivo persistence, functional activity and anti-tumor efficacy of CAR.GD2 NKTs. We will generate patient-specific CAR.GD2 NKTs and treat NB patients at four dose levels. Toxicities will be monitored according to NCI guidelines. We will also evaluate the antitumor and immunological activities of NKT-cell therapy. The results of this study will inform clinical development of NKT-cell based immunotherapy of NB and have a broad applicability for other types of cancer.
