Pediatric Hematology/Oncology, ALL-BFM Study Group, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Division of Pediatric Oncology, and Children Research Center, University Childreńs Hospital, Zurich, Switzerland.
Blood Adv. 2022 Aug 23;6(16):4847-4858. doi: 10.1182/bloodadvances.2022007364.
Immunotherapy has evolved as a powerful tool for the treatment of B-cell malignancies, and patient outcomes have improved by combining therapeutic antibodies with conventional chemotherapy. Overexpression of antiapoptotic B-cell lymphoma 2 (Bcl-2) is associated with a poor prognosis, and increased levels have been described in patients with "double-hit" diffuse large B-cell lymphoma, a subgroup of Burkitt's lymphoma, and patients with pediatric acute lymphoblastic leukemia harboring a t(17;19) translocation. Here, we show that the addition of venetoclax (VEN), a specific Bcl-2 inhibitor, potently enhanced the efficacy of the therapeutic anti-CD20 antibody rituximab, anti-CD38 daratumumab, and anti-CD19-DE, a proprietary version of tafasitamab. This was because of an increase in antibody-dependent cellular phagocytosis by macrophages as shown in vitro and in vivo in cell lines and patient-derived xenograft models. Mechanistically, double-hit lymphoma cells subjected to VEN triggered phagocytosis in an apoptosis-independent manner. Our study identifies the combination of VEN and therapeutic antibodies as a promising novel strategy for the treatment of B-cell malignancies.
免疫疗法已发展成为治疗 B 细胞恶性肿瘤的有力工具，通过将治疗性抗体与传统化疗相结合，患者的预后得到了改善。抗凋亡 B 细胞淋巴瘤 2（Bcl-2）的过度表达与预后不良相关，在“双打击”弥漫性大 B 细胞淋巴瘤、伯基特淋巴瘤的一个亚组以及携带 t（17；19）易位的儿童急性淋巴细胞白血病患者中，已描述了 Bcl-2 水平升高。在这里，我们表明，添加 venetoclax（VEN），一种特定的 Bcl-2 抑制剂，可显著增强治疗性抗 CD20 抗体利妥昔单抗、抗 CD38 达雷妥尤单抗和抗 CD19-DE（tafasilumab 的专有版本）的疗效。这是因为巨噬细胞的抗体依赖性细胞吞噬作用增加，如在细胞系和患者来源的异种移植模型中体外和体内所示。从机制上讲，VEN 处理的双打击淋巴瘤细胞以一种不依赖凋亡的方式触发吞噬作用。我们的研究确定了 VEN 和治疗性抗体的联合使用是治疗 B 细胞恶性肿瘤的一种很有前途的新策略。
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