Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy with great potential in treating relapsed or refractory B-cell cancers. However, developing effective CAR T-cell therapy for solid tumors has proven more challenging. Neuroblastoma, the most common extracranial solid tumor in children, has a poor prognosis for patients with high-risk disease at diagnosis.
Traditional treatments have limited success, and subsequent treatments have a very low probability of recovery. In previous studies, neuroblastoma cells express high levels of the disialoganglioside GD2, a target antigen successfully targeted with monoclonal antibodies. This suggests that immunotherapy may be a viable option for treating neuroblastoma. Early-phase clinical trials of GD2-targeted CAR T cells have shown feasibility, but few objective responses have been reported.
A GD2-directed CAR construct incorporating two costimulatory domains, CD28 and 4-1BB, was developed to address this issue. In addition, the gene for inducible caspase 9 (iC9) was included as a safety switch to prevent dangerous toxic effects. The results of phase 1-2 clinical trial involving patients with relapsed or refractory high-risk neuroblastoma showed promising outcomes at the three-year mark.
A new study published in the New England Journal of Medicine has reported positive results for a new immunotherapy approach for relapsed or refractory neuroblastoma. The study involved using GD2-CART01, a chimeric antigen receptor (CAR) T-cell therapy that targets GD2, a protein highly expressed on the surface of neuroblastoma cells. The therapy was tested on 19 children and young adults with relapsed or refractory neuroblastoma. The patients were given GD2-CART01 after receiving lymphodepleting chemotherapy.
The results showed that the therapy was successful in all but one of the patients, with 33% achieving a complete response and a 3-year event-free survival rate of 36% among children who received the recommended dose. The therapy induced an immune-related response, manifested by mild cytokine release syndrome in most patients. Although manageable, the side-effect profile of this type of immunotherapy is not negligible, with hematologic toxic effects being reported in every patient.
Despite the side effects, the therapy was shown to have a wide biodistribution and was detected in the cerebrospinal fluid in five patients. None of these patients had a current or a history of central nervous system disease infiltration, and none had major neurotoxic effects. The study showed that GD2-CART01 cells had a sustained clinical response, possibly due to the persistence of CAR T cells for more than 6 weeks, possibly because of the incorporation of two costimulatory domains in the construct and the use of interleukin-7 and interleukin-15 in the manufacturing of GD2-CART01.
Although the induction of an immune response against the murine single-chain variable fragment remains a possible limitation to the efficacy of multiple infusions of CAR T cells, some patients may benefit from multiple infusions, especially if these infusions are preceded by lymphodepletion.
This is an essential strategy for treating solid tumors because it counteracts the dysfunctional phenotype induced in CAR T cells by persistent antigen presentation in the context of a highly immune-suppressive microenvironment. The study shows promise for using GD2-CART01 as a potential therapy for relapsed or refractory neuroblastoma. However, further studies are needed to evaluate the efficacy and safety of this therapy in larger populations.
