Department of Internal Medicine III, University of Ulm, Helmholtzstr. 10, 89081, Ulm, Germany.
Department of Internal Medicine, Diakonie Hospital Stuttgart, Stuttgart, Germany.
Cancer Immunol Immunother. 2020 Apr;69(4):629-640. doi: 10.1007/s00262-020-02490-2. Epub 2020 Feb 4.
The efficacy of immunotherapies in cancer treatment becomes more and more apparent not only in different solid tumors but also in hematological malignancies. However, in acute myeloid leukemia (AML), mechanisms to increase the efficacy of immunotherapeutic approaches have to be further elucidated. Targeting leukemic progenitor and stem cells (LPC/LSC) by specific CTL, for instance, in an adjuvant setting or in minimal residual disease, might be an option to prevent relapse of AML or to treat MRD. Therefore, we investigated the influence of immune checkpoint inhibitors on LAA-specific immune responses by CTL against leukemic myeloid blasts and colony-forming cells including leukemic progenitor cells (CFC/LPC). In functional immunoassays like CFU/CFI (colony-forming units/immunoassays) and ELISpot analysis, we detected specific LAA-directed immune responses against CFC/LPC that are postulated to be the source population of relapse of the disease. The addition of nivolumab (anti-PD-1) significantly increases LAA-directed immune responses against CFC/LPC, no effect is seen when ipilimumab (anti-CTLA-4) is added. The combination of ipilimumab and nivolumab does not improve the effect compared to nivolumab alone. The anti-PD1-directed immune response correlates to PD-L1 expression on progenitor cells. Our data suggest that immunotherapeutic approaches have the potential to target malignant CFC/LPC and anti-PD-1 antibodies could be an immunotherapeutic approach in AML. Moreover, combination with LAA-directed vaccination strategies might also open interesting application possibilities.
免疫疗法在癌症治疗中的疗效不仅在不同的实体肿瘤中越来越明显，而且在血液恶性肿瘤中也越来越明显。然而，在急性髓系白血病（AML）中，需要进一步阐明提高免疫治疗方法疗效的机制。例如，在辅助治疗或微小残留疾病中，通过特异性 CTL 靶向白血病祖细胞和干细胞（LPC/LSC），可能是预防 AML 复发或治疗微小残留疾病的一种选择。因此，我们研究了免疫检查点抑制剂对 CTL 针对白血病髓样母细胞和包括白血病祖细胞（CFC/LPC）在内的集落形成细胞的 LAA 特异性免疫反应的影响。在 CFU/CFI（集落形成单位/免疫测定）和 ELISpot 分析等功能免疫测定中，我们检测到针对 CFC/LPC 的特异性 LAA 定向免疫反应，这些反应被认为是疾病复发的来源群体。添加 nivolumab（抗 PD-1）可显著增加针对 CFC/LPC 的 LAA 定向免疫反应，而添加 ipilimumab（抗 CTLA-4）则没有效果。与 nivolumab 单独使用相比，ipilimumab 和 nivolumab 的联合使用并不能提高效果。抗 PD-1 免疫反应与祖细胞上的 PD-L1 表达相关。我们的数据表明，免疫治疗方法有可能靶向恶性 CFC/LPC，抗 PD-1 抗体可能是 AML 的一种免疫治疗方法。此外，与 LAA 定向疫苗接种策略的联合使用也可能开辟有趣的应用可能性。
