TY - JOUR
T1 - Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL
AU - Awasthi, Rakesh
AU - Pacaud, Lida
AU - Waldron, Edward
AU - Tam, Constantine S.
AU - Jäger, Ulrich
AU - Borchmann, Peter
AU - Jaglowski, Samantha
AU - Foley, Stephen Ronan
AU - Van Besien, Koen
AU - Wagner-Johnston, Nina D.
AU - Kersten, Marie José
AU - Schuster, Stephen J.
AU - Salles, Gilles
AU - Maziarz, Richard T.
AU - Anak, Özlem
AU - Del Corral, Christopher
AU - Chu, Jufen
AU - Gershgorin, Irina
AU - Pruteanu-Malinici, Iulian
AU - Chakraborty, Abhijit
AU - Mueller, Karen Thudium
AU - Waller, Edmund K.
N1 - Funding Information:
Conflict-of-interest disclosure: R.A. is an employee of Novartis Institutes for BioMedical Research and owns stock in Cara Therapeutics, Exelixis, Ultragenyx, Aeterna Zentaris, Celgene, and Novartis Pharmaceuticals. L.P. and E.W. are employees of Novartis Pharmaceuticals Corporation, East Hanover, NJ. C.S.T. has received honoraria from Novartis and personal fees from Janssen and AbbVie. U.J. has received honoraria from AbbVie, Amgen, AOP Orphan, Celgene, Emergent, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Novartis, Roche, and Takeda–Millennium; participated in advisory roles for AbbVie, Millennium, Mundipharma, Novartis, Roche, and Celgene; and received research funding from Celgene, Emergent, Gilead, Infinity, Janssen, Mundipharma, Novartis, Roche, Takeda–Millennium, and TrueNorth Therapeutics. P.B. has received honoraria from Novartis, Takeda, Bristol-Myers Squibb, Roche, Celgene, and MSD; received research funding from Takeda; and served in an advisory or expert testimony role for Novartis, Takeda, Bristol-Myers Squibb, Roche, Amgen, and Celgene. S.J. has received research funding from Novartis and served in a consulting or advisory role for Kite and Juno. S.R.F. has received honoraria from Novartis, Celgene, and Amgen; has received travel/accommodations/expenses from Novartis and Jazz Pharmaceuticals; has served in a consulting or advisory role for Novartis; and has participated in speakers’ bureaus for Celgene and Janssen. K.v.B. has received research funding from Novartis Pharmaceuticals Corporation. N.D.W.-J. has participated in advisory boards for Bayer, Gilead, JUNO, and ADC Therapeutics. M.J.K. has received clinical trial grants/research funding from Roche, Celgene, and Millennium/Takeda and has received honoraria for speaking at satellite symposia and attending advisory boards for Novartis, Cel-gene, Roche, BMS, Amgen, Janssen, and Kite Pharma/Gilead. S.J.S. has received clinical trial grants/research funding from Novartis Pharmaceuticals Corporation, Celgene, Genentech, and Merck; has served in a consulting role for Novartis Pharmaceuticals Corporation, Celgene, Genentech, and Gilead; has participated in steering committees for Novartis Pharmaceuticals Corporation, Nordic Nanovector, and Celgene; has participated in advisory boards/committees for Celgene, Genentech, Gilead, Merck, Nordic Nanovector, Pfizer, and Pharmacyclics; has given presentations for Dava Oncology, OncLive, i3Health, and Physicians’ Education Resource, LLC; is involved in planned clinical research collaborations with Nordic Nanovector; and serves on the Scientific Board of Advisors (unpaid) for OncoViRx. G.S. has received honoraria from Janssen, Gilead, Celgene, Novartis, Amgen, Servier, BMS, Merck, MOrphosys, Roche, Acerta, Pfizer, Epizyme, and AbbVie; has served in a consulting role for Gilead, Celgene, Novartis, Amgen, Servier, BMS, Merck, MOrphosys, Roche, Acerta, Pfizer, Epizyme, and AbbVie; and serves on steering committees for Novartis. R.T.M. has received honoraria from Incyte, Kite Therapeutics, Novartis Pharmaceuticals Corporation, Juno Therapeutics, and Jazz Pharmaceuticals; has served in a consulting role for Incyte, Athersys, and CRISPR Therapeutics; has received research funding from Novartis Pharmaceuticals Corporation; has served as chair of the Scientific Steering Committee for the JULIET trial; and has a patent “Immu-nomodulary Properties of Multipotent Adult Progenitor Cells and Uses Thereof (#8,147,824)” with royalties paid to Athersys. Ö.A. is an employee of Novartis Pharma AG. C.d.C., J.C., and I.G. are employees of Novartis Pharmaceuticals Corporation. I.P.-M. and A.C. are employees of Novartis Institutes for BioMedical Research. K.T.M. is an employee of and owns stock in Novartis Pharmaceutical Corporation. E.K.W. is an employee in a leadership position with equity ownership in Cambium Medical Technologies; owns stock in Cerus Corporation and Chimerix; has received research funding from Celldex, Novartis, and Pharmacyclics; has served in a consulting or advisory role for Kalytera and Novartis; has participated in advisory committees for Novartis; and has received travel expenses from Pharmacyclics. In addition, E.K.W. has a patent “Method of allogeneic hematopoietic stem cell transplantation without graft failure or graft vs. host disease” (#5,800,539) licensed to Cerus, a patent “Mouse model with human immune system” (#6,060,643) issued, a patent “Methods for treating cancer using allogeneic lymphocytes without graft versus host disease activity” (#6,213,127) licensed to Cerus, a patent “Compositions and methods for the expression of factor VIII polypeptides and uses therefore” (#6,517,830) issued, a patent “Methods for the treatment of graft-versus-host disease” (#8,486,408) issued, a patent “Methods for managing graft versus host disease” (#9,458,217) licensed to Cambium Oncology, a patent “Antagonism of the VIP signaling pathway” (#9,669,092) licensed to Cambium Oncology, a patent “Managing Graft Versus Host Disease (GvHD) Using Indole Carboxyaldehydes or Derivatives Thereof” (US20170079950A1) issued, a patent “Compositions, uses, and preparation of platelet
Publisher Copyright:
© 2020 by The American Society of Hematology.
PY - 2020/2/11
Y1 - 2020/2/11
N2 - The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints.
AB - The anti-CD19 chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel was evaluated in the global, phase 2 JULIET study in adult patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We correlated tisagenlecleucel cellular kinetics with clinical/product parameters in 111 patients treated in JULIET. Tisagenlecleucel persistence in responders and nonresponders, respectively, was demonstrated for 554 and 400 days maximum by flow cytometry and for 693 and 374 days maximum by quantitative polymerase chain reaction (qPCR). No relationships were identified between cellular kinetics (qPCR) and product characteristics, intrinsic/extrinsic factors, dose, or immunogenicity. Most patients with 3-month response had detectable transgene at time of response and continued persistence for ≥6 months. Expansion (maximal expansion of transgene/CAR-positive T-cell levels in vivo postinfusion [Cmax]) was potentially associated with response duration but this did not reach statistical significance (hazard ratio for a twofold increase in Cmax, 0.79; 95% confidence interval, 0.61-1.01). Tisagenlecleucel expansion was associated with cytokine-release syndrome (CRS) severity and tocilizumab use; no relationships were observed with neurologic events. Transgene levels were associated with B-cell levels. Dose was associated with CRS severity, but this was not statistically significant after adjusting for baseline tumor burden. In contrast to the results from B-cell precursor acute lymphoblastic leukemia (B-ALL) and chronic lymphocytic leukemia, similar exposure was observed in DLBCL in this study regardless of response and expansion was lower in DLBCL than B-ALL, likely from differences in cancer location and/or T-cell intrinsic factors. Relationships between expansion and CRS severity, and lack of relationships between dose and exposure, were similar between DLBCL and B-ALL. Tisagenlecleucel cellular kinetics in adult relapsed/refractory DLBCL improve current understanding of in vivo expansion and its relationships with safety/efficacy endpoints.
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U2 - 10.1182/bloodadvances.2019000525
DO - 10.1182/bloodadvances.2019000525
M3 - Article
C2 - 32045475
AN - SCOPUS:85082188780
VL - 4
SP - 560
EP - 572
JO - Blood advances
JF - Blood advances
SN - 2473-9529
IS - 3
ER -