Immunotherapy of Neuroblastoma with CAR.GD2 NKT Cells

Project Goal

The overall goal of this proposal is to develop and clinically test a conceptually new form of cancer immunotherapy using native and engineered properties of Natural Killer T cells (NKTs). We found that NKTs target tumor-associated macrophages (TAMs), 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 clinical trials in NB patients that produced promising results. To ensure safety of NKT-cell therapy, we added an inducible suicide gene called iC9, which can be activated by a non-toxic drug and has been found to be safe in patients.

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. to produce and validate CAR.GD2 NKTs under GMP conditions;
2. to conduct a phase-I clinical trial of ex vivo expanded CAR.GD2 NKTs in patients with resistant/recurrent NB;
3. to 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 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.