Response-adapted zanubrutinib and tislelizumab as a potential strategy to enhance CD19 CAR T-cell therapy in relapsed/refractory large B-cell lymphoma: A retrospective observational study

Abstract

Background: CD19 chimeric antigen receptor (CAR) T-cell therapy is a potential treatment for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). The combination of targeted therapeutic strategies, particularly bruton tyrosine kinase inhibitor zanubrutinib and programmed death-1 inhibitor tislelizumab, may improve clinical outcomes and modulate the tumour microenvironment (TME).

Methods: We studied patients with R/R LBCL who received response-adapted zanubrutinib plus tislelizumab upon CD19 CAR T-cell therapy between June 2021 and March 2023. Patients were treated with zanubrutinib daily from leukapheresis to day 28 post-infusion; those achieving complete response continued zanubrutinib monotherapy for 3 months, while partial responders received combined zanubrutinib for 3 months and tislelizumab for up to 2 years. We evaluated the overall response rate (ORR), complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and safety. DNA sequencing and RNA sequencing were performed on available tumour samples to analyse genetic aberrations and TME characteristics.

Results: A total of 54 patients with LBCL were included, with a median follow-up of 23.6 months. The ORR at day 28, month 3, and month 6 were 94% (CRR 66%), 87% (CRR 80%), and 80% (CRR 76%), respectively. The 2-year PFS and 2-year OS rates were 68% and 76%, respectively. Median PFS and median OS were not reached. Grade ≥ 3 cytokine release syndrome occurred in 9% of patients, with no grade ≥ 3 neurotoxicity observed. Genomic and transcriptomic data indicated that this regimen was effective across genetic subtypes and abrogated T-cell exhaustion within the TME. However, tumour-infiltrating M2 macrophages with dysregulated lipid metabolism were associated with poor clinical outcome.

Conclusions: Response-adapted zanubrutinib and tislelizumab potentially enhances the efficacy of CAR T-cell therapy with a favourable safety profile in R/R LBCL, effectively counteracting T-cell exhaustion. Future studies should focus on targeting M2 macrophages by reprogramming lipid metabolism to further attenuate the immunosuppressive TME.

Keywords

bruton tyrosine kinase inhibitor / chimeric antigen receptor T-cell therapy / large B-cell lymphoma / programmed death-1 inhibitor / tumour microenvironment

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.