Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7)

Authors

Simone Filosto
Saran Vardhanabhuti
Miguel A Canales
Xavier Poiré
Lazaros J Lekakis
Sven de Vos
Craig A Portell
Zixing Wang
Christina To
Marco Schupp
Soumya Poddar
Tan Trinh
Carmen M Warren
Ethan G Aguilar
Justin Budka
Paul Cheng
Justin Chou
Adrian Bot
Rhine R Shen
Jason R Westin

Publication Date

1-8-2024

Journal

Blood Cancer Discovery

Abstract

Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability. In apheresis material and final product, a naive T-cell phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved response durability, event-free survival, progression-free survival, and a lower number of prior therapies. This phenotype was not associated with high-grade cytokine release syndrome (CRS) or neurologic events. Higher baseline and postinfusion levels of serum inflammatory markers associated with differentiated/effector products, reduced efficacy, and increased CRS and neurologic events, thus suggesting targets for intervention. These data support better outcomes with earlier CAR T-cell intervention and may improve patient care by informing on predictive biomarkers and development of next-generation products.

Significance: In ZUMA-7, the largest randomized CAR T-cell trial in LBCL, a naive T-cell product phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved efficacy, decreased toxicity, and a lower number of prior therapies, supporting earlier intervention with CAR T-cell therapy. In addition, targets for improvement of therapeutic index are proposed. This article is featured in Selected Articles from This Issue, p. 4

Keywords

Humans, Immunotherapy, Adoptive, CD28 Antigens, Receptors, CCR7, Lymphoma, Large B-Cell, Diffuse, Research Personnel, Cytokine Release Syndrome, Leukocyte Common Antigens

DOI

10.1158/2643-3230.BCD-23-0112

PMID

37983485

PMCID

PMC10772511

PubMedCentral® Posted Date

11-17-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes