抵抗t细胞重定向疗法的机制

IF 3.9 4区 医学 Q2 HEMATOLOGY
A. A. Alizadeh
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引用次数: 0

摘要

t细胞重定向疗法已经彻底改变了各种恶性肿瘤的治疗,特别是b细胞非霍奇金淋巴瘤。目前批准的治疗方法包括t细胞修饰表达嵌合抗原受体(CAR-T细胞)和双特异性抗体,将t细胞与多种肿瘤抗原连接起来。然而,尽管这些疗法具有显著的疗效和治疗潜力,但耐药性和复发仍然是重大障碍,不幸的是,今天在大多数患者中仍然观察到这些障碍。本报告将探讨成熟b细胞肿瘤产生这种耐药的肿瘤内在机制,同时也考虑t细胞功能障碍和肿瘤微环境(TME)在耐药表型中的作用。我将回顾几项研究的数据,这些研究强调了肿瘤内在抗性的关键机制和途径。在Sworder等人(Cancer Cell, 2023)的一项关键研究中,描述了一种综合的同步肿瘤和效应分析(STEP)方法来研究抗cd19 CAR - t细胞治疗的大b细胞淋巴瘤的耐药决定因素。除了已知的阻碍关键肿瘤标志物(如CD19、CD20、CD22和BCMA)靶抗原表达的遗传和表观遗传机制外,这些研究还揭示了B细胞识别基因(如PAX5和IRF8)的遗传改变可能导致谱系切换或靶抗原的丢失。另外,这些研究表明,体细胞增益如何驱动关键免疫检查点(如PD-L1上调)的上调,从而帮助肿瘤逃避t细胞的攻击。对于双特异性抗体,也观察到类似的机制,如抗原丢失,这表明各种治疗方法都存在共同的挑战。当考虑到非肿瘤的内在耐药机制时,TME也被认为起着至关重要的作用,研究表明免疫抑制的TME谱与较差的结果相关,可能是通过PD-1、TIM-3、Tregs、MDSCs、抑制性细胞因子等轴阻碍t细胞功能。已知由慢性抗原暴露和TME免疫抑制驱动的t细胞衰竭会降低效应剂的功能和持久性,影响CAR-T和双特异性抗体的功效。相反,具有高B细胞增殖的TMEs可能预测更好的CAR-T反应,这是一个意想不到的特征,也可以指导治疗选择。我将重点介绍这些整合基因组分析、TME分析和t细胞功能评估的方法如何提高结果预测和个性化t细胞治疗。除了定义我们目前知识中的关键差距之外,我还将描述帮助弥合这些差距的策略,以优化现有疗法和开发下一代干预措施来克服耐药性,潜在地改善淋巴瘤和其他肿瘤患者的长期预后。关键词:侵袭性b细胞非霍奇金淋巴瘤潜在利益冲突来源
本文章由计算机程序翻译,如有差异,请以英文原文为准。
MECHANISMS OF RESISTANCE TO T-CELL REDIRECTING THERAPIES

T-cell redirecting therapies, have revolutionized the management of diverse malignancies, especially B-cell non-Hodgkin lymphomas. Currently approved such therapies include T-cells that are engineered to express chimeric antigen receptors (CAR-T cells) and bispecific antibodies that bridge T-cells to diverse tumor antigens. Yet despite their remarkable efficacy and curative potential, resistance and relapse to these therapies remain significant hurdles, and unfortunately, still observed in most patients today. This presentation will explore the tumor-intrinsic mechanisms that contribute to such resistance in mature B-cell neoplasms, while also considering the roles of T-cell dysfunction and the tumor microenvironment (TME) in resistance phenotypes.

I will review data from several studies that have highlighted key mechanisms and pathways underlying such tumor intrinsic resistance. In one key study by Sworder et al. (Cancer Cell, 2023) a comprehensive simultaneous tumor and effector profiling (STEP) approach has been described to investigate resistance determinants in large B-cell lymphomas treated with anti-CD19 CAR T-cells. In addition to genetic and epigenetic mechanisms known to hamper target antigen expression of key tumor markers (such as CD19, CD20, CD22, and BCMA), these studies have revealed that genetic alterations in B cell identity genes like PAX5 and IRF8 may lead to lineage switch or loss of target antigens. Separately, these studies show how somatic gains driving upregulation of key immune checkpoints like PD-L1 upregulation can help tumors evade T-cell attacks. For bispecific antibodies, similar mechanisms, such as antigen loss, are also observed, suggesting shared challenges across therapies.

When considering non-tumor intrinsic mechanisms of resistance, the TME is also known to play a crucial role, with research indicating that immune-suppressed TME profiles correlate with poorer outcomes, likely by hindering T-cell function through axes such as PD-1, TIM-3, suppressive actions of Tregs, MDSCs, inhibitory cytokines, and others. T-cell exhaustion, driven by chronic antigen exposure and TME immunosuppression, is known to reduce effector functions and persistence, impacting both CAR-T and bispecific antibody efficacy. Conversely, TMEs with high B cell proliferation may predict better CAR-T responses, an unexpected feature that could also guide therapy selection.

I will highlight how such approaches to integrative genomic profiling, TME analysis, and T-cell functional assessments can enhance outcome prediction and personalize T-cell therapies. In addition to defining key gaps in our current knowledge, I will describe strategies to help bridge these gaps, toward optimizing existing therapies and developing next-generation interventions to overcome resistance, potentially improving long-term outcomes for patients with lymphomas and other tumors.

Keywords: aggressive B-cell non-Hodgkin lymphoma

No potential sources of conflict of interest.

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来源期刊
Hematological Oncology
Hematological Oncology 医学-血液学
CiteScore
4.20
自引率
6.10%
发文量
147
审稿时长
>12 weeks
期刊介绍: Hematological Oncology considers for publication articles dealing with experimental and clinical aspects of neoplastic diseases of the hemopoietic and lymphoid systems and relevant related matters. Translational studies applying basic science to clinical issues are particularly welcomed. Manuscripts dealing with the following areas are encouraged: -Clinical practice and management of hematological neoplasia, including: acute and chronic leukemias, malignant lymphomas, myeloproliferative disorders -Diagnostic investigations, including imaging and laboratory assays -Epidemiology, pathology and pathobiology of hematological neoplasia of hematological diseases -Therapeutic issues including Phase 1, 2 or 3 trials as well as allogeneic and autologous stem cell transplantation studies -Aspects of the cell biology, molecular biology, molecular genetics and cytogenetics of normal or diseased hematopoeisis and lymphopoiesis, including stem cells and cytokines and other regulatory systems. Concise, topical review material is welcomed, especially if it makes new concepts and ideas accessible to a wider community. Proposals for review material may be discussed with the Editor-in-Chief. Collections of case material and case reports will be considered only if they have broader scientific or clinical relevance.
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