Total body irradiation primes CD19-directed CAR T cells against large B-cell lymphoma

CD19-targeting chimeric antigen receptor T cells (CART19) have demonstrated significant effectiveness in treating relapsed or refractory large B-cell lymphoma (LBCL). However, they often fail to sustain durable remissions in more than half of all treated patients. Therefore, there is an urgent need to identify approaches to enhance CART19 efficacy. Here, we studied the impact of low-dose radiation on CART19 activity in vitro and find that radiation enhances the cytotoxicity of CART19 against LBCL by upregulating death receptors. Disrupting the FAS receptor diminishes this benefit, indicating that this pathway plays an important role in enhancing the cytotoxic effects of CAR T cells. To further validate these findings, we conducted in vivo studies using a lymphoma syngeneic mouse model delivering total body irradiation (TBI). We observed that delivering TBI at a single dose of 1Gy prior to CAR T cell infusion significantly improved CART19-mediated tumor elimination and increased overall survival rates. Importantly, we characterized several important effects of TBI, including enhanced lymphodepletion, improved T cell expansion and persistence, better intra-tumoral migration, and a more favorable, anti-tumor phenotypic composition of the T cells. In summary, for the first time, we have demonstrated preclinically that administering TBI before CART19 infusion significantly accelerates tumor elimination and improves overall survival. This approach holds promise for translation into clinical practice and serves as a valuable foundation for further research to enhance outcomes for patients receiving CART19 treatment.