肿瘤细胞治疗研究
英文原题：Bispecific Antibodies for Acute Myeloid Leukemia: From Bone Marrow Immune Niche to Clinical Translation.
急性髓系白血病（AML）是一种异质性血液系统恶性肿瘤，其特征为髓系原始细胞的克隆性扩增以及白血病干细胞（LSCs）在深度重塑的骨髓（BM）微环境中的持续存在。
急性髓系白血病（AML）是一种异质性血液系统恶性肿瘤，其特征为髓系原始细胞的克隆性扩增以及白血病干细胞（LSCs）在深度重塑的骨髓（BM）微环境中的持续存在。尽管在分子分层和靶向药物引入方面取得了进展，但长期结局仍不令人满意，尤其是在老年和高危患者中。越来越多的证据表明，白血病发生和治疗耐药在很大程度上由一种允许性免疫环境所维持，其中LSCs、髓源性抑制细胞、白血病相关巨噬细胞以及功能失调的T细胞和NK细胞共同塑造了一个免疫抑制性“白血病微环境”。这一不断深入的认识重新激发了人们对能够恢复有效抗肿瘤免疫的免疫治疗策略的兴趣。双特异性抗体（bsAbs）是经过工程化设计的分子，旨在结合AML相关抗原，同时募集并激活免疫效应细胞，最常见的是T细胞或NK细胞。通过促进免疫突触形成，且不依赖于主要组织相容性复合体的表达和传统共刺激通路，bsAbs能够克服多种免疫逃逸机制。在本综述中，我们总结了AML免疫治疗的生物学依据，重点关注BM微环境和免疫失调的作用。随后我们讨论了IgG样和非IgG样bsAbs的结构和功能特性、关键抗原靶点如CD33、CD123、CD70等，以及正在临床研究中的主要T细胞和NK细胞衔接平台。最后，我们重点介绍新兴的临床数据、主要毒性，以及将bsAbs整合到现有治疗方案中的挑战，包括与去甲基化药物、BCL-2抑制剂和异基因干细胞移植的联合治疗。更深入地理解AML免疫生物学和抗原表达模式，对于优化bsAb设计、最大化治疗获益并最小化靶向非肿瘤毒性至关重要。
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts and the persistence of leukemic stem cells (LSCs) within a profoundly remodeled bone marrow (BM) microenvironment. Despite advances in molecular stratification and the introduction of targeted agents, long-term outcomes remain unsatisfactory, particularly in older and high-risk patients. Increasing evidence indicates that leukemogenesis and treatment resistance are critically sustained by a permissive immune milieu, in which LSCs, myeloid-derived suppressor cells, leukemia-associated macrophages, and dysfunctional T and NK cells shape an immunosuppressive "leukemic niche." This evolving understanding has renewed interest in immune-based strategies capable of restoring effective antitumor immunity. Bispecific antibodies (bsAbs) are engineered molecules designed to engage AML-associated antigens while simultaneously recruiting and activating immune effector cells, most commonly T cells or NK cells. By promoting immune synapse formation independently of major histocompatibility complex expression and conventional co-stimulatory pathways, bsAbs can overcome several mechanisms of immune escape. In this review, we summarize the biological rationale for immunotherapy in AML, with a focus on the role of the BM microenvironment and immune dysregulation. We then discuss the structural and functional properties of IgG-like and non-IgG-like bsAbs, key antigenic targets such as CD33, CD123, CD70 and others, and the main T-cell- and NK-cell-engaging platforms under clinical investigation. Finally, we highlight emerging clinical data, principal toxicities, and the challenges of integrating bsAbs into existing treatment algorithms, including combinations with hypomethylating agents, BCL-2 inhibitors, and allogeneic stem cell transplantation. A deeper understanding of AML immune biology and antigen expression patterns will be essential to optimize bsAb design, maximize therapeutic benefit, and minimize on-target off-tumor toxicity.
MEMBER ACCOUNT
登录成功会直接打开下一页。
