Tumour immune contexture is a determinant of anti-CD19 CAR T-cell efficacy in large B cell lymphoma

Axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory large B-cell lymphoma (LBCL), has comparable efficacy across conventional LBCL markers. We analysed whether pre- and posttreatment tumour immune contexture determines clinical outcomes for axi cel–treated patients in the ZUMA-1 pivotal study. Longitudinal evaluation of the tumour microenvironment (TME) uncovered dynamic patterns that occurred rapidly after axi-cel (within 2 weeks) in responders—pronounced enhancement of T- and myeloid cell signatures and diminution of B cell signature. Clinical response and overall survival associated with high CD8+ T-cell density (Immunoscore) and immune gene expression (Immunosign21) in TME pretreatment, which was paralleled by blood CAR T-cell levels posttreatment. High density of regulatory T cells in TME pretreatment associated with reduced axi-cel–related neurologic toxicity. At relapse, the TME evolved toward an immune-detrimental contexture with decreased T-cell–related and increased counterregulatory immune signatures and B cell lineage antigens. A TME rich in T-cell attractive chemokines (CCL5, CCL22), gamma-chain receptor cytokines (IL-15, IL-7, IL-21), and interferon regulated molecules associated with T-cell infiltration and markers of activity, a result validated in 2 independent datasets totalling ≈300 LBCL samples. These findings advance mechanistic understanding of CAR T-cell therapy and foster biomarker development and treatment optimizations. 71 samples were analyzed for 65 patients with screening, baseline, DAY7-14, FCBWK4 and PROGFCB time points.