TY - JOUR
T1 - Tisagenlecleucel immunogenicity in relapsed/refractory acute lymphoblastic leukemia and diffuse large B-cell lymphoma
AU - Mueller, Karen Thudium
AU - Grupp, Stephan A.
AU - Maude, Shannon L.
AU - Levine, John E.
AU - Pulsipher, Michael A.
AU - Boyer, Michael W.
AU - August, Keith J.
AU - Doug Myers, G.
AU - Tam, Constantine S.
AU - Jaeger, Ulrich
AU - Foley, Stephen Ronan
AU - Borchmann, Peter
AU - Schuster, Stephen J.
AU - Waller, Edmund K.
AU - Awasthi, Rakesh
AU - Potthoff, Bernd
AU - Warren, Andy
AU - Waldron, Edward R.
AU - McBlane, Fraser
AU - Chassot-Agostinho, Andrea
AU - Laetsch, Theodore W.
N1 - Funding Information:
Conflict-of-interest disclosure: 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, Genen-tech/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,
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.
Publisher Copyright:
© 2021 American Society of Hematology. All rights reserved.
PY - 2021/12/14
Y1 - 2021/12/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85121745174&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2020003844
DO - 10.1182/bloodadvances.2020003844
M3 - Article
C2 - 34432863
AN - SCOPUS:85121745174
VL - 5
SP - 4980
EP - 4991
JO - Blood advances
JF - Blood advances
SN - 2473-9529
ER -