Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas

Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudi-nal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabta-gene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvi-ronment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.

Automated summary

This study investigates the resistance of anti-CD19 chimeric antigen receptor (CAR19) T cells in relapsed/refractory large B-cell lymphoma (r/rLBCL) patients. By analyzing longitudinal samples from two independent cohorts, it identifies multiple gene alterations associated with resistance, such as B cell identity genes (PAX5 and IRF8), immune checkpoint genes (CD274), and genes affecting the tumor microenvironment (TMEM30A). It also reveals that somatic tumor alterations affect CAR19 therapy at various levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. These findings have implications for improving CAR T cells and personalized therapeutic approaches.