Abstract
Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) Tcells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n= 65 and n= 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free Tcell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered Tcell 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 microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 Tcell expansion, persistence, and tumor microenvironment. Further, CAR19 Tcells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) Tcells and personalized therapeutic approaches.
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