CD19.CAR T Cells(University Hospital Heidelberg)

We report a phase 1 study assessing the safety and efficacy of CD19 chimeric antigen receptor (CAR) T cells as definitive consolidation in older adults (aged ≥55 years) with B-cell acute lymphoblastic leukemia (B-ALL) in first complete remission (CR1). Eighteen patients received lymphodepletion followed by infusion of memory-enriched CD19 CAR T cells. The median age was 64 years, and all patients were measurable residual disease (MRD)–negative before lymphodepletion. There were no dose-limiting toxicities, grade ≥2 cytokine release syndrome, or any grade immune effector cell–associated neurotoxicity syndrome. Estimated 18-month event-free and overall survival were 84% and 100%, respectively. CAR T cells expanded in the blood and cerebrospinal fluid despite patients’ MRD-negative status. Comparing clinical samples from patients with relapsed/refractory (R/R) B-ALL from our historical trial (ClinicalTrials.gov identifier: NCT02146924) and patients in CR1, we found that the blood and CAR T-cell products from patients with R/R B-ALL were hyperinflammatory and hyperimmunometabolic, respectively. First-line CAR T-cell therapy was safe and well tolerated and potentially extended remission in patients in MRD-negative CR1. These findings support further investigation of the early use of CAR T-cell therapy for B-ALL. This trial was registered at www.clinicaltrials.gov as NCT05707273.

Chimeric antigen receptor (CAR) T cell therapy induces durable remissions in lymphoid malignancies, yet the extent and biology of long-term CAR T cell persistence in B cell lymphoma remain unclear. Here we report the persistence and characteristics of 4-1BB-costimulated anti-CD19 CAR T cells (CART19) up to 10 years after infusion in 38 patients with non-Hodgkin lymphoma. Beyond year five, the CAR19 transgene was detectable in five of eight long-term responders (7.0–10.1 years), with three patients maintaining B cell aplasia, which is consistent with sustained functional activity. In one patient with a progression-free survival of 10.1 years, CART19 cells comprised 1.2% of circulating T cells 9.3 years after infusion. Long-term persisting CART19 cells exhibited a predominant double-negative (CD4 − CD8 − ), effector-memory-like phenotype associated with increased aerobic metabolism and T cell activation programs. Longitudinal profiling revealed a progressive transition from CD8 + to double-negative CAR T cells over time. Persisting CART19 shared transcriptional features with long-term CAR T cells described in acute and chronic leukemias. T cell receptor sequencing demonstrated oligoclonal persistence at 9.3 years, with a dominant clone (70% of CART19 cells) already detectable at low frequency (<0.1%) at day 14. Lentiviral integration-site analysis identified a predominant integration within PACS1 without evidence of known drivers of CAR T cell expansion. These findings demonstrate that CART19 cells can persist for more than 10 years in lymphoma and identify phenotypic, transcriptional and clonal features associated with exceptionally long-term persistence. ClinicalTrials.gov registration: NCT02030834