Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor Responses In Vivo.
Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor Responses In Vivo.
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DOI：
10.1158/1535-7163.mct-21-0035
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发表时间：
2021-10
影响因子：
5.7
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中科院分区：
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b细胞成熟抗原（BCMA）是一种在多发性骨髓瘤和其他b细胞恶性肿瘤分化浆细胞上高表达的有吸引力的治疗靶点。GSK2857916 （belantamab mafodotin， BLENREP）是一种靶向bcma的抗体-药物偶联物，被批准用于治疗复发/难治性多发性骨髓瘤。我们报道GSK2857916在体外和体内诱导表达bcma的癌细胞的免疫原性细胞死亡，并促进树突状细胞的活化。在表达人BCMA （EL4- hbcma）的EL4淋巴瘤肿瘤中，GSK2857916治疗可增强肿瘤内免疫细胞的浸润和激活，延缓肿瘤生长，并促进持久的完全消退。应答小鼠对EL4亲本细胞和EL4- hbcma细胞的再攻击免疫，这表明适应性免疫反应、免疫记忆和肿瘤抗原扩散参与其中，这些在内源性CD8+ T细胞耗尽后被消除。与OX40/OX86（一种免疫激动剂抗体）联合，显著增强抗肿瘤活性并增加持久的完全应答，为GSK2857916与靶向适应性免疫应答的免疫疗法（包括t细胞导向的检查点调节剂）联合的临床评估提供了强有力的依据。
B-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody–drug conjugate approved for the treatment of relapsed/refractory multiple myeloma. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo. GSK2857916 treatment enhances intratumor immune cell infiltration and activation, delays tumor growth, and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to rechallenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8+ T cells. Combinations with OX40/OX86, an immune agonist antibody, significantly enhance antitumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell–directed checkpoint modulators.