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

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-04-23 DOI:10.1002/ctm2.70310

Rong Shen, Wei-Guo Cao, Li Wang, Ling-Shuang Sheng, Yi-Lun Zhang, Wen Wu, Peng-Peng Xu, Shu Cheng, Meng-Ke Liu, Yan Dong, Yue Wang, Xiang-Qin Weng, Xu-Feng Jiang, Qi Song, Hong-Mei Yi, Lei Li, Sheng Chen, Zi-Xun Yan, Wei-Li Zhao

{"title":"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","authors":"Rong Shen, Wei-Guo Cao, Li Wang, Ling-Shuang Sheng, Yi-Lun Zhang, Wen Wu, Peng-Peng Xu, Shu Cheng, Meng-Ke Liu, Yan Dong, Yue Wang, Xiang-Qin Weng, Xu-Feng Jiang, Qi Song, Hong-Mei Yi, Lei Li, Sheng Chen, Zi-Xun Yan, Wei-Li Zhao","doi":"10.1002/ctm2.70310","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>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).</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>\n <p>Response-adapted zanubrutinib plus tislelizumab potentially enhances the efficacy of CAR T-cell therapy for R/R LBCL with acceptable safety profile.</p>\n </li>\n \n <li>\n <p>This regimen functions independently of genetic subtypes, rendering it more applicable for clinical practice with CAR T-cell therapy.</p>\n </li>\n \n <li>\n <p>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.</p>\n </li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 4","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70310","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70310","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

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.

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.

Abstract Image

查看原文本刊更多论文

反应适应性扎鲁替尼和替舒利珠单抗是加强复发/难治性大B细胞淋巴瘤CD19 CAR T细胞疗法的潜在策略：一项回顾性观察研究

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。靶向治疗策略的结合，特别是布鲁顿酪氨酸激酶抑制剂zanubrutinib和程序性死亡-1抑制剂tislelizumab，可能改善临床结果并调节肿瘤微环境（TME）。研究人员研究了在2021年6月至2023年3月期间接受适应反应的zanubrutinib + tislelizumab CD19 CAR - t细胞治疗的R/R LBCL患者。从白细胞分离到输注后第28天，患者每天接受扎鲁替尼治疗；达到完全缓解的患者继续zanubrutinib单药治疗3个月，而部分缓解者接受zanubrutinib联合治疗3个月和tislelizumab联合治疗长达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。对现有肿瘤样本进行DNA和RNA测序，分析遗传畸变和TME特征。结果共纳入54例LBCL患者，中位随访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和2年OS率分别为68%和76%。中位PFS和中位OS均未达到。9%的患者出现≥3级细胞因子释放综合征，未观察到≥3级神经毒性。基因组学和转录组学数据表明，该方案在遗传亚型中有效，并消除了TME内的t细胞衰竭。然而，伴脂质代谢失调的肿瘤浸润性M2巨噬细胞与较差的临床结果相关。结论：适应反应的zanubrutinib和tislelizumab可能增强CAR - t细胞治疗在R/R LBCL中的疗效，具有良好的安全性，有效地抵消t细胞衰竭。未来的研究应侧重于通过重编程脂质代谢来靶向M2巨噬细胞，进一步减轻免疫抑制性TME。适应反应的zanubrutinib + tislelizumab可能增强CAR - t细胞治疗R/R LBCL的疗效，并具有可接受的安全性。该方案独立于基因亚型发挥作用，使其更适用于CAR - t细胞治疗的临床实践。该方案有效地消除了t细胞衰竭，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细胞治疗提供了理论依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.