Shen Rong, Cao Wei-Guo, Wang Li, Sheng Ling-Shuang, Zhang Yi-Lun, Wu Wen, Xu Peng-Peng, Cheng Shu, Liu Meng-Ke, Dong Yan, Wang Yue, Weng Xiang-Qin, Jiang Xu-Feng, Song Qi, Yi Hong-Mei, Li Lei, Chen Sheng, Yan Zi-Xun, Zhao Wei-Li
Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Radiation Oncology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Clin Transl Med. 2025 Apr;15(4):e70310. doi: 10.1002/ctm2.70310.
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.
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.
CD19嵌合抗原受体（CAR）T细胞疗法是复发/难治性（R/R）大B细胞淋巴瘤（LBCL）的一种潜在治疗方法。靶向治疗策略的联合应用，特别是布鲁顿酪氨酸激酶抑制剂泽布替尼和程序性死亡-1抑制剂替雷利珠单抗，可能改善临床结局并调节肿瘤微环境（TME）。
我们研究了2021年6月至2023年3月期间接受CD19 CAR T细胞治疗后采用适应性泽布替尼加替雷利珠单抗治疗的R/R LBCL患者。患者从白细胞分离术到输注后第28天每天接受泽布替尼治疗；达到完全缓解的患者继续接受泽布替尼单药治疗3个月，而部分缓解者接受泽布替尼联合治疗3个月和替雷利珠单抗治疗长达2年。我们评估了总缓解率（ORR）、完全缓解率（CRR）、无进展生存期（PFS）、总生存期（OS）和安全性。对可用肿瘤样本进行DNA测序和RNA测序，以分析基因畸变和TME特征。
共纳入54例LBCL患者，中位随访时间为23.6个月。第28天、第3个月和第6个月的ORR分别为94%（CRR 66%）、87%（CRR 80%）和80%（CRR 76%）。2年PFS率和2年OS率分别为68%和76%。未达到中位PFS和中位OS。9%的患者发生≥3级细胞因子释放综合征，未观察到≥3级神经毒性。基因组和转录组数据表明，该方案对各基因亚型均有效，并消除了TME内的T细胞耗竭。然而，脂质代谢失调的肿瘤浸润M2巨噬细胞与不良临床结局相关。
适应性泽布替尼和替雷利珠单抗可能增强CAR T细胞疗法在R/R LBCL中的疗效，且安全性良好，有效对抗T细胞耗竭。未来的研究应聚焦于通过重新编程脂质代谢来靶向M2巨噬细胞，以进一步减弱免疫抑制性TME。
适应性泽布替尼加替雷利珠单抗可能增强CAR T细胞疗法对R/R LBCL的疗效，安全性可接受。该方案的作用不依赖于基因亚型，使其更适用于CAR T细胞疗法的临床实践。该方案有效消除T细胞耗竭，但未能克服M2巨噬细胞的免疫抑制作用，为重塑TME以优化CAR T细胞疗法提供了理论依据。
