Rausch Johanna, Ullrich Evelyn, Kühn Michael W M
Department of Hematology and Medical Oncology, University Medical Center, Johannes Gutenberg-University, Mainz, Germany.
German Cancer Consortium (DKTK) Partner Site Frankfurt/Mainz and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Front Immunol. 2023 Sep 22;14:1269012. doi: 10.3389/fimmu.2023.1269012. eCollection 2023.
AML is a malignant disease of hematopoietic progenitor cells with unsatisfactory treatment outcome, especially in patients that are ineligible for intensive chemotherapy. Immunotherapy, comprising checkpoint inhibition, T-cell engaging antibody constructs, and cellular therapies, has dramatically improved the outcome of patients with solid tumors and lymphatic neoplasms. In AML, these approaches have been far less successful. Discussed reasons are the relatively low mutational burden of AML blasts and the difficulty in defining AML-specific antigens not expressed on hematopoietic progenitor cells. On the other hand, epigenetic dysregulation is an essential driver of leukemogenesis, and non-selective hypomethylating agents (HMAs) are the current backbone of non-intensive treatment. The first clinical trials that evaluated whether HMAs may improve immune checkpoint inhibitors' efficacy showed modest efficacy except for the anti-CD47 antibody that was substantially more efficient against AML when combined with azacitidine. Combining bispecific antibodies or cellular treatments with HMAs is subject to ongoing clinical investigation, and efficacy data are awaited shortly. More selective second-generation inhibitors targeting specific chromatin regulators have demonstrated promising preclinical activity against AML and are currently evaluated in clinical trials. These drugs that commonly cause leukemia cell differentiation potentially sensitize AML to immune-based treatments by co-regulating immune checkpoints, providing a pro-inflammatory environment, and inducing (neo)-antigen expression. Combining selective targeted epigenetic drugs with (cellular) immunotherapy is, therefore, a promising approach to avoid unintended effects and augment efficacy. Future studies will provide detailed information on how these compounds influence specific immune functions that may enable translation into clinical assessment.
急性髓系白血病（AML）是一种造血祖细胞的恶性疾病，治疗效果不尽人意，尤其是对于那些不符合强化化疗条件的患者。免疫疗法，包括检查点抑制、T细胞衔接抗体构建体和细胞疗法，已显著改善了实体瘤和淋巴瘤患者的治疗结果。在AML中，这些方法的成功率要低得多。讨论的原因包括AML原始细胞相对较低的突变负担以及难以定义造血祖细胞上未表达的AML特异性抗原。另一方面，表观遗传失调是白血病发生的重要驱动因素，非选择性低甲基化剂（HMAs）是目前非强化治疗的主要手段。评估HMAs是否能提高免疫检查点抑制剂疗效的首批临床试验显示疗效一般，不过抗CD47抗体与阿扎胞苷联合使用时对AML的疗效显著更高。将双特异性抗体或细胞疗法与HMAs联合使用正在进行临床研究，不久将获得疗效数据。针对特定染色质调节因子的更具选择性的第二代抑制剂已在临床前研究中显示出对AML有前景的活性，目前正在进行临床试验评估。这些通常会导致白血病细胞分化的药物可能通过共同调节免疫检查点、提供促炎环境和诱导（新）抗原表达，使AML对基于免疫的治疗敏感。因此，将选择性靶向表观遗传药物与（细胞）免疫疗法相结合是一种有前景的方法，可以避免意外影响并提高疗效。未来的研究将提供关于这些化合物如何影响特定免疫功能的详细信息，这可能有助于转化为临床评估。
