Tisagenlecleucel immunogenicity in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma

• Type of Material: Article
• Authors: Karen T. Mueller, Novartis Institutes for BioMedical Research; Stephan A. Grupp, University of Pennsylvania; Shannon L. Maude, University of Pennsylvania; John E. Levine, University of Michigan; Michael A. Pulsipher, University of Southern California; Michael W. Boyer, University of Utah; Keith J. August, Childrens Mercy Hospital; G. Doug Myers, Childrens Mercy Hospital; Constantine S. Tam, Royal Melbourne Hospital; Ulrich Jaeger, Medical University of Vienna; Stephen Ronan Foley, McMaster University; Peter Borchmann, University Hospital Cologne; Stephen J. Schuster, University of Pennsylvania; Edmund Waller, Emory University; Rakesh Awasthi, Novartis Institutes for BioMedical Research; Bernd Potthoff, Novartis Pharma AG; Andy Warren, Salt River Integrated Bioanalysis GmbH; Edward R. Waldron, Novartis Pharmaceuticals Corporation; Fraser McBlane, Novartis Pharma AG; Andrea Chassot-Agostinho, Novartis Pharmaceuticals Corporation; Theodore W. Laetsch, University of Pennsylvania
• Language: English
• Date: 2021-12-03
• Publisher: Elsevier
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by The American Society of Hematology.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2020003844
• Title of Journal or Parent Work: Blood Advances
• Volume: 5
• Issue: 23
• Start Page: 4980
• End Page: 4991
• Grant/Funding Information: Medical writing support was for this manuscript was funded by Novartis Pharmaceuticals Corporation. The studies presented herein were sponsored by Novartis Pharmaceuticals Corporation.
• Keywords: Antibodies; Science & Technology; Kinects; Clinical pharmacology; Hematology; Products; Life Sciences & Biomedicine; T-cells
• Research Categories: Health Sciences, Oncology; Biology, Cell; Health Sciences, Pharmacology

Abstract

Tisagenlecleucel is indicated for pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL). The tisagenlecleucel chimeric antigen receptor (CAR) contains a murine single-chain variable fragment domain; we examined the effects of humoral and cellular immune responses to tisagenlecleucel on clinical outcomes using 2 validated assays. Data were pooled from the ELIANA (registered at www.clinicaltrials.gov as #NCT02435849) and ENSIGN (#NCT02228096) trials in r/r B-ALL (N 5 143) and the JULIET trial (#NCT02445248) in r/r DLBCL (N 5 115). Humoral responses were determined by flow cytometric measurement of anti-murine CAR19 (mCAR19) antibodies in serum. Cellular responses were determined using T-cell production of interferon-g in response to 2 different pools of mCAR19 peptides. Pretreatment anti-mCAR19 antibodies were detected in 81% of patients with r/r B-ALL and 94% of patients with r/r DLBCL. Posttreatment anti-mCAR19 antibodies were higher than patient-specific baseline in 42% of r/r B-ALL and 9% of r/r DLBCL patients. Pretreatment and posttreatment anti-mCAR19 antibodies did not affect tisagenlecleucel cellular kinetics, including maximum concentration and persistence (r2 , 0.05), clinical response (day-28 response, duration of response, and event-free survival), and safety. T-cell responses were consistent over time, with net responses ,1% at baseline and posttreatment time points in a majority of patients and no effect on transgene expansion or persistence or outcomes. Presence of baseline and/or posttreatment anti-mCAR19 antibodies or T-cell responses did not alter the activity of tisagenlecleucel in patients with r/r B-ALL or r/r DLBCL.