Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia
| Autor: | Michael A. Pulsipher, Carl H. June, Jason Hamilton, Shannon L. Maude, Michael Boyer, Rakesh Awasthi, Bruce L. Levine, Keith J. August, Lori Tomassian, Mimi Leung, Theodore W. Laetsch, Andrew M. Stein, Edward Waldron, Sweta Shah, Tetiana Taran, Denise Sickert, Karen Thudium Mueller, Abhijit Chakraborty, Stephan A. Grupp, Patricia A. Wood, John E. Levine |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Oncology Cancer Research medicine.medical_specialty Adolescent medicine.medical_treatment Antigens CD19 Cell- and Tissue-Based Therapy Receptors Antigen T-Cell Cmax Immunotherapy Adoptive Article law.invention Mice Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Tocilizumab Antigen law Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Internal medicine medicine Animals Humans Lymphocyte Count Transgenes Child Clinical pharmacology business.industry Immunogenicity Genetic Therapy Immunotherapy Prognosis medicine.disease Chimeric antigen receptor Immunity Humoral Cytokine release syndrome Treatment Outcome 030104 developmental biology chemistry Child Preschool 030220 oncology & carcinogenesis Female business |
| Zdroj: | Clin Cancer Res |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-18-0758 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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