More than a decade after its discovery, advances have been made in understanding the oncogenic role of mutantCALRinBCR::ABL1-negative myeloproliferative neoplasms (MPNs). Disease biology has proven to be distinct from other MPN subtypes, with meaningful differences that have created opportunities for therapeutic targeting ofCALR-mutant clones. Among the approaches under investigation, immunotherapy has advanced furthest into clinical development and holds promise. Several strategies are now being explored, including monoclonal antibodies directed against the CALR neoepitope, T-cell–redirecting bispecific antibodies, precision antibody–drug conjugates, vaccination approaches, and CAR T-cell therapies. Early-phase clinical trials with fully human anti-CALR monoclonal antibodies (e.g., INCA033989) have shown very promising hematologic and molecular responses with manageable toxicity. In preclinical models, bispecific antibodies and CAR T-cell therapy offer additional avenues to exploit the selective cell-surface localization of mutant CALR. By contrast, vaccination strategies have so far demonstrated limited clinical efficacy, and their potential in clinical practice remains challenging. At the same time, the complexity ofCALR-driven disease raises key questions, including whether anti-CALR therapies can shift treatment goals beyond thrombotic risk reduction, how best to monitor clonal burden, and how to address immune escape. In this review, we highlight the latest therapeutic advances inCALR-mutated MPNs while outlining the critical unmet needs that will shape the future of care for these patients.
自突变CALR在BCR::ABL1阴性骨髓增殖性肿瘤（MPNs）中的致癌作用被发现十余年来，相关研究已取得显著进展。该疾病生物学特征已被证实与其他MPN亚型存在本质区别，其关键差异为靶向CALR突变克隆的治疗创造了契机。在诸多研究策略中，免疫治疗已进入临床开发的最前沿并展现出广阔前景。目前正在探索的方案包括：靶向CALR新表位的单克隆抗体、T细胞重定向双特异性抗体、精准抗体药物偶联物、疫苗接种策略以及CAR T细胞疗法。针对全人源抗CALR单克隆抗体（如INCA033989）的早期临床试验已显示出极具前景的血液学及分子学应答，且毒性可控。在临床前模型中，双特异性抗体与CAR T细胞疗法为利用突变CALR选择性细胞表面定位特性提供了新途径。相比之下，疫苗接种策略迄今临床疗效有限，其在临床实践中的应用潜力仍面临挑战。与此同时，CALR驱动疾病的复杂性引发了一系列关键问题：抗CALR疗法能否将治疗目标拓展至降低血栓风险之外？如何优化克隆负荷监测方案？以及如何应对免疫逃逸现象？本综述将重点阐述CALR突变MPNs的最新治疗进展，同时指出影响未来诊疗方向的关键未满足需求。
肿瘤(癌症)患者之家