Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia.
Immune Dysfunctions and Immune-Based Therapeutic Interventions in Chronic Lymphocytic Leukemia.
复制标题
慢性淋巴细胞白血病的免疫功能障碍和免疫治疗干预。
DOI：
10.3389/fimmu.2020.594556
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发表时间：
2020
影响因子：
7.3
通讯作者：
Coscia M
中科院分区：
文献类型：
--
作者：
Griggio V;Perutelli F;Salvetti C;Boccellato E;Boccadoro M;Vitale C;Coscia M
慢性淋巴细胞白血病（CLL）是一种B细胞恶性肿瘤，其特征在于广泛的肿瘤诱导的改变，其影响免疫应答的先天性和适应性臂，并在疾病进展期间积累。近年来，靶向治疗的发展，如B细胞受体信号传导抑制剂和Bcl-2蛋白抑制剂venetoclax，极大地改变了CLL的治疗前景。尽管靶向药物具有显著的抗肿瘤活性，但仍存在一些局限性，包括耐药机制的发展以及在高危患者中观察到的疗效较差。因此，额外的治疗是必要的，以获得更深的反应和克服耐药性。利用免疫介导的移植物抗白血病效应来根除肿瘤细胞的异基因造血干细胞移植（HSCT）目前代表了CLL患者的唯一潜在治愈性治疗选择。然而，由于其潜在的毒性，HSCT只能提供给有限数量的年轻和健康的患者。对肿瘤细胞和免疫系统之间复杂相互作用的理解不断加深，这为免疫逃逸机制和肿瘤进展铺平了道路。尽管有很好的临床前观察结果，但探索新型免疫疗法安全性和有效性的试点临床研究的结果有时在长期肿瘤控制方面并不理想。因此，需要进一步的进展来提高其功效。在这种情况下，可能的方法包括在治疗序列中更早地安排免疫治疗，以及通过将免疫治疗剂与其他抗肿瘤药物联合施用来提高免疫治疗剂的功效的可能性。在这篇综述中，我们将全面概述影响CLL患者的主要免疫缺陷，并描述导致免疫逃避和肿瘤进展的复杂网络。从治疗的角度来看，我们将经历基于免疫的治疗方法随时间的演变，包括i）具有广泛免疫调节作用的药物，如免疫调节药物，ii）目前批准的和下一代单克隆抗体，以及iii）旨在激活或施用特异性靶向白血病细胞的免疫效应细胞的免疫抑制策略（例如双特异性或三特异性抗体、肿瘤疫苗、嵌合抗原受体T细胞和检查点抑制剂）。
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a wide range of tumor-induced alterations, which affect both the innate and adaptive arms of the immune response, and accumulate during disease progression. In recent years, the development of targeted therapies, such as the B-cell receptor signaling inhibitors and the Bcl-2 protein inhibitor venetoclax, has dramatically changed the treatment landscape of CLL. Despite their remarkable anti-tumor activity, targeted agents have some limitations, which include the development of drug resistance mechanisms and the inferior efficacy observed in high-risk patients. Therefore, additional treatments are necessary to obtain deeper responses and overcome drug resistance. Allogeneic hematopoietic stem cell transplantation (HSCT), which exploits immune-mediated graft-versus-leukemia effect to eradicate tumor cells, currently represents the only potentially curative therapeutic option for CLL patients. However, due to its potential toxicities, HSCT can be offered only to a restricted number of younger and fit patients. The growing understanding of the complex interplay between tumor cells and the immune system, which is responsible for immune escape mechanisms and tumor progression, has paved the way for the development of novel immune-based strategies. Despite promising preclinical observations, results from pilot clinical studies exploring the safety and efficacy of novel immune-based therapies have been sometimes suboptimal in terms of long-term tumor control. Therefore, further advances to improve their efficacy are needed. In this context, possible approaches include an earlier timing of immunotherapy within the treatment sequencing, as well as the possibility to improve the efficacy of immunotherapeutic agents by administering them in combination with other anti-tumor drugs. In this review, we will provide a comprehensive overview of main immune defects affecting patients with CLL, also describing the complex networks leading to immune evasion and tumor progression. From the therapeutic standpoint, we will go through the evolution of immune-based therapeutic approaches over time, including i) agents with broad immunomodulatory effects, such as immunomodulatory drugs, ii) currently approved and next-generation monoclonal antibodies, and iii) immunotherapeutic strategies aiming at activating or administering immune effector cells specifically targeting leukemic cells (e.g. bi-or tri-specific antibodies, tumor vaccines, chimeric antigen receptor T cells, and checkpoint inhibitors).