Neuroblastoma is the most common, extracranial, solid tumor cancer in children, and patients with high-risk disease are challenging to treat. In a promising development, researchers at Baylor College of Medicine announced a phase 1, first-in-human clinical trial of a new form of immunotherapy to treat neuroblastoma using genetically engineered natural killer T cells (NKTs).

Dr. Andras Heczey, assistant professor of pediatrics-hematology and oncology, and Dr. Leonid Metelitsa, professor of pediatrics-oncology at Baylor College of Medicine, have studied neuroblastoma for years with the goal of making research breakthroughs that lead to new therapies. Neuroblastoma affects the nervous system, which consists of the brain, spinal cord, and the nerves that extend from these tissues to all areas of the body. The nervous system is essential for thinking, sensation, and movement, among other crucial functions.

“Neuroblastoma is a challenging tumor type, and this clinical trial is addressing a significant need in the treatment of pediatric solid tumors,” Heczey said. “Our goal is to find a safe option to effectively treat high-risk neuroblastoma.”

NKTs are a subgroup of white blood cells that can enter tumor tissues and indirectly suppress tumor growth by attacking tumor-supportive macrophages. GD2 is a molecule that is found on the surface of almost all neuroblastoma cells.

Heczey, Metelitsa, and colleagues have genetically engineered NKTs to express a protein known as the GD2-specific chimeric antigen receptor (GD2-CAR), which enables these immune cells to directly kill neuroblastoma cells by targeting GD2. The GD2-CAR construct also includes a mediator known as interleukin-15, which should enable NKTs to function better in the low-oxygen tumor microenvironment and last longer following infusion into patients.

“GD2-CAR-engineered NKTs recognize GD2 on the cell surface of neuroblastoma cells, which they destroy specifically and effectively in the laboratory setting while maintaining the ability to indirectly attack neuroblastoma by eliminating tumor-associated macrophages,” Heczey said. “There is tremendous promise in this therapy, and this clinical trial will help us determine how to best implement it for patients.”

The key aims of the clinical trial are to establish the maximum tolerated dose of GD2-CAR NKTs, evaluate their effect on the tumor, measure how long they can be detected in the patient’s blood, and characterize their effect on the patient’s neuroblastoma.

These aims will be accomplished by generating GD2-CAR NKTs directly from the blood of individual neuroblastoma patients and then re-infusing the engineered cells back into the patient. Toxicities will be monitored according to NCI guidelines.

Voluntary enrollment for the gene transfer research study using these special immune cells is currently open to patients whose neuroblastoma has either come back after treatment or has not responded to the standard, existing therapies and medicines used to treat it.

“I’m very excited about bringing the first-in-human clinical testing of CAR-redirected NKTs to children with neuroblastoma,” Metelitsa said. “It took nearly 15 years from our discovery of NKT presence in tumors and their association with favorable outcomes in neuroblastoma patients to developing a clinical-grade therapeutic product, which combines natural and engineered antitumor properties of NKTs.”