In Situ CD19.CAR-T Generation Using TRIDENT System for Pediatric B Cell Malignancies
Cancer is the leading cause of death by disease for children in the United States, and B cell malignancy is the most common form of childhood cancer, accounting for more than 30% of all childhood cancers. Although outcomes in pediatric patients with B cell lymphoma have improved in recent decades, with survival rates of >80%, relapse or progression are nearly universally fatal for children and young adults with relapsed and refractory mature B cell lymphoma. Genetically modified chimeric antigen receptor expressing T cells targeting CD19 (CD19.CAR-T cells) have been a paradigm shift for pediatric patients with B cell malignancies, leading to 80% complete response rates and the first FDA approved CAR-T cell product for pediatric patients. However, FDA approved CD19.CAR-T cell products are derived from patients’ own T cells (autologous), limiting the availability of this therapy due to cost, time to treatment, and difficulty in manufacturing products. To overcome these limitations, the field of cell-based therapies is moving toward allogeneic “off-the-shelf” cell products by utilizing recent genetic modification technologies. However, clinical trials using allogeneic CD19.CAR-T cells were halted for safety concerns, including patient death. Thus, there is an urgent need to develop platforms that would be immediately applicable for all pediatric patients with B cell malignancies and be immediately available for use in the clinic without requiring advanced equipment that may not be accessible outside of a major medical facility.
Our long-term objective is to increase the availability of life-saving CD19.CAR-T cell therapy for pediatric patients with a more accessible and ready to use “off-the-shelf” helper-dependent adenoviral vector platform (TRIDENT), overcoming the limitations of current adoptively transferred autologous CD19.CAR-T cells. We will achieve this goal by directly generating CD19.CAR-T cells within patient's lymph node (autologous) with injection of our “off-the-shelf” TRIDENT to cure B cell malignancies in pediatric patients. Since TRIDENT would be immediately available and administered by simple injection, the risk of cancer progression and the immense burden put upon pediatric patients and their families as well as the cost of treatment would be greatly reduced.