Local radiation enhances systemic CAR T-cell efficacy by augmenting antigen crosspresentation and T-cell infiltration

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CART-19) represents a significant advance in the treatment of patients with relapsed or refractory CD19+ B-cell lymphomas. However, a significant portion of patients either relapse or fail to respond. Moreover, many patients have symptomatic disease, requiring bridging radiation therapy (RT) during the period of CAR T-cell manufacturing. To investigate the impact of 1 to 2 fractions of low-dose RT on CART-19 treatment response, we developed a mouse model using A20 lymphoma cells for CART-19 therapy. We found that low-dose fractionated RT had a positive effect on generating abscopal systemic antitumor responses beyond the irradiated site. The combination of RT with CART-19 therapy resulted in additive effects on tumor growth in irradiated masses. Notably, a significant additional increase in antitumor effect was observed in nonirradiated tumors. Mechanistically, our results validate activation of the cyclic guanosine adenosine synthetase/stimulator of interferon genes pathway, tumor-associated antigen crosspriming, and elicitation of epitope spreading. Collectively, our findings suggest that RT may serve as an optimal priming and bridging modality for CAR T-cell therapy, overcoming treatment resistance and improving clinical outcomes in patients with CD19+ hematologic malignancies. The submission includes RNA-seq data from tumor and lymph nodes samples collected form BALB/c mice bearing two A20 lymphoma tumors, one primary treated with radiation therapy (RT) (IR tumor) and one non-treated (Non-IR tumor). The primary objective was to assess the gene expression profiles in response to different RT regiments, a sinlge dose of 8Gy or 2 regiments of 4Gy. The samples were collected 24 hours and 7 days post RT treatment. Each experimental group includes 2 or 3 bilogical replicates, except the lymph nodes samples that are three biological replicates pooled together as one sample.