About this item:

59 Views | 38 Downloads

Author Notes:

Correspondence: Karen T. Mueller, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936; e-mail: karentmueller@gmail.com

Author contributions: S.A.G., S.L.M, J.E.L., M.A.P., M.W.B., K.J.A., G.D.M, C.S.T., U.J., S.R.F., P.B., S.J.S., E.K.W., and T.W.L. enrolled patients, performed research, and contributed to data collection and interpretation; K.T.M., R.A., B.P., A.W., E.R.W., and F.M. performed cellular kinetic and/or statistical analyses and contributed to data interpretation;

A.C.-A. contributed to data interpretation; K.T.M. wrote the first draft; all authors were involved in revising the manuscript and approved the final version; and all authors were involved in the clinical trials and had access to the primary data.

Acknowledgements: The authors thank the patients and families enrolled in this study as well as the investigators and study site personnel. Medical writing support was provided by Michael Hobert (Healthcare Consultancy Group).

The authors also thank Grzegorz Terszowski and Denise Sickert for bioanalytic support and/or thoughtful discussions, Sebastian Spindeldreher at Integrated Biologix GmbH (Basel, Switzerland) for technical and scientific contributions to the immunogenicity assays, Maloy Mangada at Cambridge Biomedical for cellular immunogenicity analyses, and Janet Stegehuis and Henko Tadema at PRA for humoral immunogenicity analyses.

Disclosures: K.T.M. is an employee of and owns stock in Novartis. S.A.G. reports grants and personal fees from Novartis; personal fees from Adaptimmune, Jazz Pharmaceuticals, TCR2 Therapeutics, Eureka Therapeutics, Cellectis, Roche, Juno Therapeutics, and Vertex; and grants from Servier and Kite and has been issued a patent for toxicity management for antitumor activity of CARs. S.L.M. reports clinical trial support from Novartis; consulting, advisory boards, or study steering committee for Novartis, Kite, and Wugen.

J.E.L., K.J.A., and C.S.T. report personal fees from Novartis. M.A.P. reports grants from Adaptive; personal fees from Novartis, Adaptive, CSL Behring, and Amgen; and nonfinancial support from Medac and Amgen. G.D.M. reports consultancy for Novartis. U.J. reports grants and personal fees from Novartis, Gilead, Celgene/Bristol-Myers Squibb, and Miltenyi. S.J.S. reports personal fees and honoraria from Acerta, AlloGene, AstraZeneca, BeiGene, Genentech/Roche, LoxoOncology, Novartis, and Tessa Therapeutics;

Consulting fees from Celgene/Juno; honoraria from Celgene, Nordic Nanovector, and Pfizer; steering committee participation for AbbVie, Celgene, Novartis, Juno, Nordic Nanovector, and Pfizer; and research support from AbbVie, Acerta, Celgene/Juno, DTRM Bio, Genentech, Incyte, Merck, Novartis, Portola, and TG Therapeutics and holds a patent for combination therapies of CAR and PD-1 inhibitors (royalties to Novartis).

E.K.W. reports research grants from Novartis, Celldex, Partners Therapeutic, Juno, and Amgen and consulting fees from Cambium Medical Technologies, Novartis, Partners Therapeutics, Pharmacyclics, and CellDx and owns stock in Cerus, Chimerix, Cambium Medical Technologies, and Cambium Oncology. R.A. is an employee of Novartis Institutes for BioMedical Research and owns stocks in Novartis Pharmaceuticals.

B.P. is an employee of and owns stock in Novartis. E.R.W. reports employment by Novartis and owns stock in Novartis. F.M. is an employee of and owns stock in Novartis. A.C.-A. is an employee of Novartis. T.W.L. reports personal fees from Novartis, Cellectis, Bayer, Loxo Oncology, and Eli Lilly; nonfinancial support from Novartis; and grants from Novartis, Pfizer, and Bayer. The remaining authors declare no competing financial interests.

Subjects:

Research Funding:

Medical writing support was for this manuscript was funded by Novartis Pharmaceuticals Corporation. The studies presented herein were sponsored by Novartis Pharmaceuticals Corporation.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • Clinical pharmacology
  • T-cells
  • Antibodies
  • Products
  • Kinects

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

Show all authors Show less authors

Tools:

Journal Title:

Blood Advances

Volume:

Volume 5, Number 23

Publisher:

, Pages 4980-4991

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2021 by The American Society of Hematology.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/rdf).
Export to EndNote