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Simple Summary: Bridging therapy (BT) in the form of systemic therapy (ST), radiation therapy (RT), or combined-modality therapy (CMT) is increasingly being utilized prior to chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). Prior institutional experiences with BT, and RT in particular, suggest it does not lead to increased toxicity or compromise outcomes. Further investigation of the optimal use of BT is warranted. In this research, we sought to evaluate the impact of BT in a large institutional cohort of patients who received commercial CAR T-cell therapy for LBCL, specifically examining the effect of BT modality and disease burden on outcomes. Here, we report the long-term outcomes of our CAR T cohort. The patients with limited disease treated with RT had favorable outcomes. Prospective studies are warranted to better characterize the optimal management of patients with relapsed/refractory LBCL who are planning to undergo CAR T-cell therapy to optimize treatment. Background: Bridging therapy (BT) with systemic therapy (ST), radiation therapy (RT), or combined-modality therapy (CMT) is increasingly being utilized prior to chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL). We report the long-term outcomes of the patients who received commercial CAR T-cell therapy with or without BT. Methods: The patients with LBCL who underwent infusion of a commercial CD19 CAR T product were eligible. The radiation was stratified as comprehensive or focal. The efficacy outcomes and toxicity were analyzed. Results: In total, 156 patients were included and, of them, 52.5% of the patients received BT. The median progression-free survival (PFS) was 0.65 years in the BT cohort compared to 1.45 years in the non-BT cohort. The median overall survival (OS) was 3.16 years in the BT cohort and was not reached in the non-BT cohort. The patients who received comprehensive radiation (versus focal) had significantly improved PFS and OS, achieving a 1-year PFS of 100% vs. 9.1% and 1-year OS of 100% vs. 45.5%. There was no difference in the severe toxicity between any of the nonbridging or BT cohorts. Conclusions: BT did not appear to compromise outcomes with respect to response rates, disease control, survival, and toxicity. The patients with limited disease treated with RT had favorable outcomes. [ABSTRACT FROM AUTHOR]

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 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 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 microenvironment (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. [Display omitted] • Tumors and CAR T cell effectors can be simultaneously profiled using cell-free DNA • Alterations in multiple classes of genes influence outcomes after CAR19 therapy • Tumor genotype and phenotype influence CAR19 T cell expansion, and vice versa • A multivariable model incorporating tumor and effector features predicts outcomes Sworder et al. develop and apply a tool to simultaneously profile tumor and effector-mediated determinants of resistance to anti-CD19 CAR T cells using cell-free DNA. The authors profile two independent cohorts of patients with relapsed/refractory large B cell lymphoma and identify genomic alterations, molecular thresholds, and microenvironmental changes associated with resistance. [ABSTRACT FROM AUTHOR]