Natural Killer T cells with an IL-15-armored GD2-specific CAR for Children with Neuroblastoma
Co-principal investigator: Leonid Metelitsa, MD/PhD
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.
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.
Project Update (May 2019)
ALSF research grantee Andras A. Heczey, MD from the Baylor College of Medicine made huge leaps forward in the search for cures for relapsed high-risk or refractory neuroblastoma.
At the Annual Meeting of the American Society of Gene & Cell Therapy in April, Dr. Heczey shared the groundbreaking success story of two patients enrolled in a phase I clinical trial for GD2-CAR NKT cell immunotherapy. The trial makes use of a patient’s own Natural Killer T-cells, which are extracted, modified and injected into the patient.
The first two patients enrolled in the trial had widely metastatic disease. Like most patients battling relapsed neuroblastoma, they had been through several unsuccessful treatments and were close to exhausting all options.
After a four-week follow-up, one patient had a stable disease. The second patient had one tumor disappear and a second tumor appeared to shrink. Neither patient experienced serious side effects from receiving the GD2-CAR NKT cell immunotherapy.
The groundwork for Dr. Heczey’s Clinical Trial was first laid through a 2014 ALSF Young Investigator grant to study the potential for NKT cell immunotherapy. This work also built off of the work of Dr. Heczey’s co-principal investigator Dr. Leonid Metelitsa.
Forbes magazine covered his early results here.