应答适应性 zanubrutinib 联合 tislelizumab 作为增强复发/难治性大 B 细胞淋巴瘤 CD19 CAR-T 细胞治疗的潜在策略：一项回顾性观察性研究

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).

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.

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.

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. HIGHLIGHTS: Response-adapted zanubrutinib plus tislelizumab potentially enhances the efficacy of CAR T-cell therapy for R/R LBCL with acceptable safety profile. This regimen functions independently of genetic subtypes, rendering it more applicable for clinical practice with CAR T-cell therapy. This regimen effectively abrogates T-cell exhaustion, but fails to overcome the immunosuppressive effects of M2 macrophages, providing a rationale for remodelling TME to optimise CAR T-cell therapy.