Lisocabtagene maraleucel outcome in large B-cell lymphoma associates with memory composition and mitochondrial fitness of T cells

CD19-directed chimeric antigen receptor (CAR) T-cell therapy enables long-term survival for patients with relapsed or refractory large B-cell lymphoma, yet fewer than half achieve durable remission. In vivo CAR T-cell expansion and persistence relate to clinical outcome and depend on underlying T-cell metabolic states, but correlative analyses linking phenotype and metabolism to T-cell expansion kinetics within a single licensed CAR T-cell product remain limited. Here, we describe a hypothesis-generating study connecting metabolic readouts to CAR T-cell expansion kinetics and treatment outcome after lisocabtagene maraleucel (liso-cel). We profiled the metabolic and phenotypic features of apheresis-derived T-cell starting material (SMAT) and liso-cel CAR T-cell products from 34 patients enrolled in the TRANSCEND-NHL-001 trial. This included 17 responders and 17 nonresponders. Samples from 3 age-matched healthy donors (HD) were included as descriptive reference. Patient SMAT contained more differentiated T-cell subsets than that from HD, whereas SMAT from responding patients were enriched for CD27 + CD8 + T cells. Liso-cel drug products were relatively uniform across patients, whereas spare respiratory capacity was higher in products from nonresponders. Higher mitochondrial potential in SMAT T cells correlated with early CAR T-cell expansion parameters, including early expansion kinetics. Transcriptomic analyses of an independent data set provided supportive context, showing increased expression levels of electron transport chain–related genes in primary T cells from responding patients. These findings provide a biologically coherent link between apheresis-level T-cell fitness and CAR T-cell expansion dynamics, supporting further evaluation of apheresis-derived biomarkers. This trial was registered at www.clinicaltrials.gov as NCT02631044 .