Cellular kinetics of CTL019 in relapsed/refractory B-cell acute lymphoblastic leukemia and chronic lymphocytic leukemia
- 23 November 2017
- journal article
- Published by American Society of Hematology in Blood
- Vol. 130 (21), 2317-2325
- https://doi.org/10.1182/blood-2017-06-786129
Abstract
Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow, using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater maximal concentration and area under the curve values compared with nonresponding patients (P < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described here are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy.Keywords
This publication has 28 references indexed in Scilit:
- Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic LeukemiaScience Translational Medicine, 2014
- CD3ζ-based chimeric antigen receptors mediate T cell activation viacis- andtrans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapyClinical and Experimental Immunology, 2014
- 4-1BB Signaling Activates the T Cell Factor 1 Effector/β-Catenin Pathway with Delayed Kinetics via ERK Signaling and Delayed PI3K/AKT Activation to Promote the Proliferation of CD8+ T CellsPLOS ONE, 2013
- Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid LeukemiaNew England Journal of Medicine, 2013
- The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemiaHaematologica, 2013
- Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid LeukemiaNew England Journal of Medicine, 2011
- T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced LeukemiaScience Translational Medicine, 2011
- Chimeric Antigen Receptor Therapy for B-cell MalignanciesJournal of Cancer, 2011
- “MIATA”—Minimal Information about T Cell AssaysImmunity, 2009
- Chimeric Receptors Containing CD137 Signal Transduction Domains Mediate Enhanced Survival of T Cells and Increased Antileukemic Efficacy In VivoMolecular Therapy, 2009