Using GD2-CART01 cells to treat neuroblastoma in pediatric patients
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Reviewed by Dat Tien Nguyen, B.A, ScM.
Translated by An Duc Thien Le |
Posted on April 17th, 2023
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Neuroblastoma is one of the most common causes of cancer death in pediatric patients. Disialoganglioside GD2 is highly expressed by neuroblastoma cells; thus, monoclonal antibody treatment has yielded positive outcomes. T-cells with chimeric antigen receptors, also known as CAR-T cells, is the novel method of cancer treatment; the T-cells were engineered to express receptors that can bind to specific cellular antigen and induce death in the expressing cell. Thus, the Italian Medicines Agency had sponsored a study to investigate the effect of the GD2-CART01 CAR-T cells in treating neuroblastoma
Besides its ability to bind to the GD-2 antigen, the CAR construct included a CD28 and a 4-1BB domain that can bind to costimulatory ligands on the cancer cells to facilitate the anti-tumor response. As a fail-safe the GD2-CART01 cells were engineered to express an inducible caspase 9 (iC9) that can be activated if the CAR-T cells are causing too much collateral damage to the host.
The result published in the New England Journal of Medicine included data from a phase 1 and a phase 2 clinical trial. The former was performed with the purpose of finding the most appropriate dose between 3, 6, and 10 million GD2-CART01 cells per kilogram of body weight. Due to the lack of difference in toxic effect between the three agent concentrations, the highest dose, 10 million GD2-CART01 cells per kilogram of body weight, was chosen as the most effective and safe dose for the next phase.
The phase 2 clinical trial included 27 children between the age of 2 and 18 years old who were diagnosed with neuroblastoma and had previously been treated with first line therapy in the form of monoclonal antibodies but had either relapsed or refracted. Most of the patients have tumors with a diameter larger than 5 cm; the cancer of these patients have metastasized and have infiltrated into the bone marrow for most patients. Before the CAR-T cells are infused intravenously, fludarabine–cyclophosphamide chemotherapy was initiated to deplete the patient’s existing lymphocytes. The health status of the children were follow-up for 3 years, and the response rate in those treated with GD2-CART01 was determined to be 63%: complete termination of the tumor was observed in 33% of the patients, and partial response was observed in 30%. The survival rate of those treated with GD2-CART01 was determined to be 60%, and the event-free survival rate was 36%. In terms of safety, the GD2-CART01 treatment leads to cytokine release syndrome in 20 out of the 27 patients (74%); in most cases, the adverse event was mild, and the activation of inducible caspase 9 was only required in 1 patient.
Besides its ability to bind to the GD-2 antigen, the CAR construct included a CD28 and a 4-1BB domain that can bind to costimulatory ligands on the cancer cells to facilitate the anti-tumor response. As a fail-safe the GD2-CART01 cells were engineered to express an inducible caspase 9 (iC9) that can be activated if the CAR-T cells are causing too much collateral damage to the host.
The result published in the New England Journal of Medicine included data from a phase 1 and a phase 2 clinical trial. The former was performed with the purpose of finding the most appropriate dose between 3, 6, and 10 million GD2-CART01 cells per kilogram of body weight. Due to the lack of difference in toxic effect between the three agent concentrations, the highest dose, 10 million GD2-CART01 cells per kilogram of body weight, was chosen as the most effective and safe dose for the next phase.
The phase 2 clinical trial included 27 children between the age of 2 and 18 years old who were diagnosed with neuroblastoma and had previously been treated with first line therapy in the form of monoclonal antibodies but had either relapsed or refracted. Most of the patients have tumors with a diameter larger than 5 cm; the cancer of these patients have metastasized and have infiltrated into the bone marrow for most patients. Before the CAR-T cells are infused intravenously, fludarabine–cyclophosphamide chemotherapy was initiated to deplete the patient’s existing lymphocytes. The health status of the children were follow-up for 3 years, and the response rate in those treated with GD2-CART01 was determined to be 63%: complete termination of the tumor was observed in 33% of the patients, and partial response was observed in 30%. The survival rate of those treated with GD2-CART01 was determined to be 60%, and the event-free survival rate was 36%. In terms of safety, the GD2-CART01 treatment leads to cytokine release syndrome in 20 out of the 27 patients (74%); in most cases, the adverse event was mild, and the activation of inducible caspase 9 was only required in 1 patient.