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Ibrutinib-based therapy reinvigorates CD8 T cells compared to chemoimmunotherapy: immune-monitoring from the E1912 trial

Papazoglou, Despoina; Wang, Victoria; Shanafelt, Tait D; Lesnick, Connie; Ioannou, Nikolaos; De Rossi, Giulia; Herter, Sylvia; ... Ramsay, Alan G; + view all (2024) Ibrutinib-based therapy reinvigorates CD8 T cells compared to chemoimmunotherapy: immune-monitoring from the E1912 trial. Blood , 143 (1) pp. 57-63. 10.1182/blood.2023020554. Green open access

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Abstract

Bruton's tyrosine kinase Inhibitors (BTKis) that target B cell receptor signaling have led to a paradigm shift in CLL treatment. BTKis have been shown to reduce abnormally high CLL-associated T cell counts and the expression of immune checkpoint receptors concomitantly with tumor reduction. However, the impact of BTKi therapy on T cell function has not been fully characterized. Here, we performed longitudinal immunophenotypic and functional analysis of pre- and on-treatment (6- and 12-months) peripheral blood samples from patients in the phase 3 E1912 trial comparing ibrutinib-rituximab to fludarabine, cyclophosphamide and rituximab (FCR). Intriguingly, we report that despite reduced overall T cell counts, higher numbers of T cells including effector CD8+ subsets at baseline and at the 6-month time-point associated with no infections and favorable progression-free survival (PFS) in the ibrutinib-rituximab arm. Assays demonstrated enhanced anti-CLL T cell killing function during ibrutinib-rituximab, including a switch from predominantly CD4+ T-cell:CLL immune synapses at baseline to increased CD8+ lytic synapses on-therapy. Conversely, in the FCR arm, higher T cell numbers correlated with adverse clinical responses and showed no functional improvement. We further demonstrate the potential of exploiting rejuvenated T cell cytotoxicity during ibrutinib-rituximab using the bispecific antibody glofitamab - supporting combination immunotherapy approaches.

Type: Article
Title: Ibrutinib-based therapy reinvigorates CD8 T cells compared to chemoimmunotherapy: immune-monitoring from the E1912 trial
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood.2023020554
Publisher version: https://doi.org/10.1182/blood.2023020554
Language: English
Additional information: Copyright © 2024 American Society of Hematology. Licensed under Creative Commons Attribution-Non Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, non derivative use with attribution. All other rights reserved.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10179713
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