Immune hematology

Neuroblastoma is the most common extracranial solid cancer in children, and patients with high-risk disease are challenging to treat. In a promising development, researchers at Baylor College of Medicine released initial findings from the first two patients treated in 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).

Extracranial solid cancer

The findings were presented today at the annual American Society of Cell & Gene Therapy (ASGCT) Meeting. Dr. Andras Heczey, assistant professor of pediatrics hematology and oncology, and Dr. Leonid Metelitsa; professor of pediatrics  oncology, both at Baylor College of Medicine and Texas Children’s Hospital; have studied NKTs and neuroblastoma for years with the goal of making research breakthroughs that lead to new therapies.

“This trial marks the first time highly pure and genetically engineer NKTs are being evaluate in humans to define their safety parameters and measure antitumor activity. For both patients thus far; these infusions have been safe and very well tolerated; further boosting our enthusiasm,” Heczey said.

Suppress tumor growth

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 find on the surface of almost all neuroblastoma cells. Heczey; Metelitsa and colleagues have genetically engineer NKT cells 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. Therefore “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 their ability to indirectly attack neuroblastoma by eliminating tumor-associated macrophages;” Heczey said.

Tumor-associated macrophages

“There is tremendous promise in this therapy; and this clinical trial is helping to 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 NKT cells; 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 are being accomplished by generating GD2-CAR NKTs directly from the blood of individual neuroblastoma patients and then re-infusing the engineer cells back into the patient. Because Toxicities are monitor according to NCI guidelines. “I’m very excited about reporting the first results of this clinical testing of CAR-redirect NKT cells in children with neuroblastoma;” Metelitsa said. “It took more than 15 years from when we discovered NKT cell presence in tumors and their association with favorable outcomes in neuroblastoma patients.