PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) 
T-cell therapy approved for the treatment of children and young adults with 
relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).
PATIENTS AND METHODS: We evaluated the cellular kinetics of tisagenlecleucel, 
the effect of patient factors, humoral immunogenicity, and manufacturing 
attributes on its kinetics, and exposure-response analysis for efficacy, safety 
and pharmacodynamic endpoints in 79 patients across two studies in pediatric 
B-ALL (ELIANA and ENSIGN).
RESULTS: Using quantitative polymerase chain reaction to quantify levels of 
tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher 
tisagenlecleucel expansion in peripheral blood than nonresponders (N = 8; 74% 
and 104% higher geometric mean Cmax and AUC0-28d, respectively) with persistence 
measurable beyond 2 years in responding patients. Cmax increased with occurrence 
and severity of cytokine release syndrome (CRS). Tisagenlecleucel continued to 
expand and persist following tocilizumab, used to manage CRS. Patients with 
B-cell recovery within 6 months had earlier loss of the transgene compared with 
patients with sustained clinical response. Clinical responses were seen across 
the entire dose range evaluated (patients ≤50 kg: 0.2 to 5.0 × 106/kg; patients 
>50 kg: 0.1 to 2.5 × 108 CAR-positive viable T cells) with no relationship 
between dose and safety. Neither preexisting nor treatment-induced antimurine 
CAR19 antibodies affected the persistence or clinical response.
CONCLUSIONS: Response to tisagenlecleucel was associated with increased 
expansion across a wide dose range. These results highlight the importance of 
cellular kinetics in understanding determinants of response to chimeric antigen 
receptor T-cell therapy.