Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia

Abstract

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). 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). Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders ( = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders ( = 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 × 10/kg; patients >50 kg: 0.1 to 2.5 × 10 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. 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.

Impaired tumor death receptor signaling drives resistance to CAR T cell therapy

“…Tisagenlecleucel expansion and persistence are highly associated with clinical response 26,27 and based on our pre-clinical observations we hypothesized that exposure to death receptor-impaired leukemia may correlate with dysfunctional T cell expansion and persistence in patients.…”

The role of clinical pharmacology across novel treatment modalities

“…This genetically modified autologous T-cell immunotherapy reprograms a patient's own T cells with a transgene encoding a chimeric antigen receptor (CAR) specific for the B-cell antigen CD19 via a lentiviral vector and shows the potential for cure in hematologic malignancies. 4 The transgene was measured and reported using a quantitative PCR assay 5,6 with a lower limit of quantification of 50 copies/μg of DNA. During assay development, regulatory guidance had cited lower limit of quantification criteria of 1% highlighting how requirements may change during development.…”

Role of CAR-T cell therapy in B-cell acute lymphoblastic leukemia

“…Using quantitative polymerase chain reaction (PCR) to quantify levels of tisagenlecleucel, responding patients (n = 62/79) of two studies in pediatric B-ALL had an approximately 2-fold higher tisagenlecleucel expansion in peripheral blood (PB) than nonresponders with persistence measurable beyond 2 years in responding patients [7]. Clinical responses were observed across the entire dose range evaluated with no relationship between cell dose and safety.…”