T cell leukemias and lymphomas represent a class of devastating cancers with high rates of relapse and mortality in both children and adults for which there are currently no effective or targeted therapies. Despite advances in Chimeric Antigen Receptor (CAR)-T cell immunotherapy for B cell malignancies, several challenges have limited development of CAR-T against T cell malignancies. This is primarily due to the shared expression of antigens on normal T cells and malignant cells. We used gene editing to develop an ‘off-the-shelf’ CAR-T product against T cell acute lymphoblastic leukemia (T-ALL) that does not have the risk of CAR-T cells attacking each other or non-cancer cells in the patient. This proposal is aimed at further optimizing CAR-T to treat T cell malignancies as studied using pre-clinical models. Additionally, we will develop therapeutic strategies to overcome life-threatening cytokine release syndrome (CRS), the major limitation of adoptive T cell immunotherapies in general.
Proposed specific aims
• Aim 1: To generate optimal CAR-T for targeting T cell malignancies
• Aim 2: To test the efficacy of pharmacologic and genetic approaches to mitigate CAR-T mediated cytokine release syndrome (CRS) while maintaining robust anti-leukemic activity
Potential impact on child health
These studies will potentially yield the ‘first-in-man’ CAR-T therapy for children with relapsed T cell hematologic malignancies. The next step will be to test this approach in a clinical trial. In addition, successful identification of new genetic and/or pharmacologic approaches to mitigate cytokine release syndrome will expand the clinical use of CAR-T and advance in this field in general.