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ORIGINAL RESEARCH article

Front. Oncol.
Sec. Hematologic Malignancies
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1519473
This article is part of the Research Topic Host Features Affecting CAR T Cell Therapy of Hematological Malignancies View all articles

Tumor Gene Expression Signatures Associated with Outcome in Large B-Cell Lymphoma Treated With CD19-directed CAR T-Cell Therapy (Axicabtagene Ciloleucel)

Provisionally accepted
Yuan Tian Yuan Tian 1Justin Budka Justin Budka 1Frederick L Locke Frederick L Locke 2Jason R. Westin Jason R. Westin 3Christina To Christina To 1Gayatri Tiwari Gayatri Tiwari 1Daqin Mao Daqin Mao 1Davide Bedognetti Davide Bedognetti 1Rhine R Shen Rhine R Shen 1Jorge Andrade Jorge Andrade 1Simone Filosto Simone Filosto 1*
  • 1 Kite Pharma, a Gilead Company, Santa Monica (CA), United States
  • 2 Moffitt Cancer Center, Tampa, Florida, United States
  • 3 University of Texas MD Anderson Cancer Center, Houston, Texas, United States

The final, formatted version of the article will be published soon.

    CAR-T cell therapy provided transformative outcomes for patients with B cell lymphoma, however a large fraction of patients remains at risk for relapse, underlying the need to uncover mechanisms of resistance and predictive biomarkers. Herein we leveraged the ZUMA-7 phase III randomized trial of relapsed/refractory large B cell lymphoma (LBCL) patients treated with axicabtagene ciloleucel (axi-cel; CD19-targeting CAR-T cells) to discover tumor gene expression signatures (GES) associated with outcome. With tumor transcriptomics from 134 axicel patients, we employed multivariate penalized Cox models analyzing event-free survival (EFS), progression-free survival (PFS), and duration of response (DOR) and identified two novel GES. A 6-gene/transcript signature (6-GES; CD19, CD45RA, CCL22, KLRK1, SOX11, SIGLEC5) correlated with improved outcome after axi-cel (HR: 0.27, 95% CI: 0.16-0.44 for EFS), representing lymphomas with abundant target antigen (CD19) expression, adhesion molecules, and relatively low immune infiltration mostly comprised of cytotoxic lymphocytes (T and NK cells) and DCs.

    Keywords: Conversely, a 17-gene/transcript signature (17-GES; CD45RO, BCL2, IL-18R1, TNFSF4 [OX40L], KLRB1 [CD161], KIR3DL2, ITGB8

    Received: 29 Oct 2024; Accepted: 03 Feb 2025.

    Copyright: © 2025 Tian, Budka, Locke, Westin, To, Tiwari, Mao, Bedognetti, Shen, Andrade and Filosto. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Simone Filosto, Kite Pharma, a Gilead Company, Santa Monica (CA), United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.