Tisagenlecleucel cellular kinetics, dose, and immunogenicity in relation to clinical factors in relapsed/refractory DLBCL

• Type of Material: Article
• Authors: Rakesh Awasthi, Novartis Institutes for BioMedical Research; Lida Pacaud, Novartis Pharmaceuticals Corporation; Edward Waldron, Novartis Pharmaceuticals Corporation; Constantine S. Tam, University of Melbourne; Ulrich Jager, Medical University of Vienna; Peter Borchmann, University Hospital Cologne; Samantha Jaglowski, Ohio State University; Stephen Ronan Foley, McMaster University; Koen van Besien, Weill Cornell Medical College; Nina D. Wagner-Johnston, Johns Hopkins University; Marie Jose Kersten, University of Amsterdam; Stephen J. Schuster, University of Pennsylvania; Giles Salles, Hospices Civils de Lyon; Richard T. Maziarz, Oregon Health and Science University; Ozlem Anak, Novartis Pharmaceuticals Corporation; Christopher del Corral, Novartis Pharmaceuticals Corporation; Jufen Chu, Novartis Pharmaceuticals Corporation; Irina Gershgorin, Novartis Pharmaceuticals Corporation; Iulian Pruteanu-Malinici, Novartis Institutes for BioMedical Research; Abhijit Chakraborty, Novartis Institutes for BioMedical Research; Karen Thudium Mueller, Novartis Institutes for BioMedical Research; Edmund Waller, Emory University
• Language: English
• Date: 2020-02-11
• Publisher: AMER SOC HEMATOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by The American Society of Hematology.
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2019000525
• Title of Journal or Parent Work: BLOOD ADVANCES
• Volume: 4
• Issue: 3
• Start Page: 560
• End Page: 572
• Keywords: THERAPY; Life Sciences & Biomedicine; T-CELLS; Hematology; Science & Technology; CTL019; B-CELL
• Research Categories: Biology, Cell

Abstract

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.