Chimeric Antigen Receptor T-cell Therapy for Neuroblastoma
GD2 is a complex sugar — a ganglioside — found on the surface of neuroblastoma cells, making it a good choice for targeted CAR T-cell therapy. GD2 is already being targeted by a recently FDA-approved immunotherapeutic drug called dinutuximab, an antibody that sticks to GD2 and activates the immune response to destroy the cell.
In previous clinical trials, dinutuximab increased survival in children with high-risk neuroblastoma by 20 percent. It is presently standard of care for high-risk neuroblastoma. Despite its effectiveness, however, it is associated with a significant amount of pain during its infusion, as GD2 receptors are also located on peripheral nerves.
Though dinutuximab has increased the survival rate in children with high-risk neuroblastoma by 20 percent, it binds to the GD2 receptors on peripheral nerves. This causes such significant neuropathy that pain management medications are administered concomitantly for the four- or five-day duration of treatment.
David M. Barrett, MD, PhD, and researchers at the Center for Childhood Cancer Research are developing CAR T-cell therapy for neuroblastoma in hopes of upping the survival rate past the 55 percent upper limit seen with dinutuximab. They are also aiming to target GD2 on the neuroblastoma cells, but not the peripheral nerves. This is a challenge, particularly taking into account the fact that CAR T-cell therapy involves permanent modification of T-cells.
Once T-cells are modified and reinfused, they divide perpetually and cannot be removed from the body. Dinutuximab is an antibody that is limited in its distribution and is cleared by the body after infusion stops.
CAR-modified T-cells are not; they can go many places simple antibodies cannot, and they cannot be cleared post-infusion.
In attempt to limit the life of the modified T-cells for this CART therapy, researchers are using RNA — rather than DNA — to modify the T-cells. Over time, RNA cannot sustain replication the way DNA can, and it will degrade, rendering the CAR-modified T-cell incapable of indefinite replication.
Using RNA transfection, researchers are creating a short-term CART therapy to assess its safety and efficacy. If the therapy is safe, i.e., not associated with GD2-mediated peripheral neuropathy, subsequent efforts will be made to make permanent alterations to the genome of the T-cells for continuous endogenous management of neuroblastoma.
These efforts are part of a Stand Up to Cancer, St. Baldrick’s Foundation Pediatric Immunogenomics Dream Team grant, a four-year grant awarded to The Children’s Hospital of Philadelphia and six other centers. This effort is being conducted across all cancer types and will hopefully lead to identification of specific cellular surface antigens that can be targeted by CART therapy. This has the potential to decrease the future need for more toxic anticancer therapies such as chemotherapy and radiation therapy.