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.
Clinical cancer research : an official journal of the American Association for Cancer Research
Adolescent; Adult; Animals; Antigens, CD19; Cell- and Tissue-Based Therapy; Child; Child, Preschool; Female; Genetic Therapy; Humans; Immunity, Humoral; Immunotherapy, Adoptive; Lymphocyte Count; Male; Mice; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Receptors, Antigen, T-Cell; Transgenes; Treatment Outcome; Young Adult
Mueller, Karen Thudium; Waldron, Edward; Grupp, Stephan A.; Levine, John E.; Laetsch, Theodore W.; Pulsipher, Michael A.; Boyer, Michael W.; August, Keith; Hamilton, Jason; Awasthi, Rakesh; Stein, Andrew M.; Sickert, Denise; Chakraborty, Abhijit; Levine, Bruce L.; June, Carl H.; Tomassian, Lori; Shah, Sweta S.; Leung, Mimi; Taran, Tetiana; Wood, Patricia A.; and Maude, Shannon L., "Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia." (2018). Manuscripts, Articles, Book Chapters and Other Papers. 1318.