肿瘤细胞治疗研究
英文原题：Characterising how a single bout of exercise in people with myeloma affects clonal plasma cell and immune effector cell frequency in blood, and daratumumab efficacy in vitro.
运动在体外适度提高了 daratumumab 介导的 ADCC 的疗效。
多发性骨髓瘤是一种血液系统癌症，特征为骨髓中克隆性浆细胞积聚，常使用抗 CD38 单克隆抗体免疫疗法 daratumumab 治疗。Daratumumab 常无法诱导严格完全缓解，部分原因是自然杀伤（NK）细胞和单核细胞介导的抗体依赖性细胞毒作用（ADCC）存在耐药。健康人运动后血液中的淋巴细胞（包括 NK 和 B 细胞）增多，但运动对骨髓瘤患者的影响尚不清楚。此外，运动是否会动员浆细胞尚未充分研究，因此运动对 daratumumab 治疗的潜在影响也不明确。在这项探索性先导研究中，16 名冒烟型多发性骨髓瘤参与者入组，9 名完成研究。参与者在高于无氧阈值 15% 的强度下骑车 30 分钟，并在运动前、运动后即刻和运动后 30 分钟采集血样。分离外周血单个核细胞，与 RPMI-8226 浆细胞瘤细胞系共孵育，有或无 daratumumab，通过 calcein 释放实验测定特异性裂解。运动前后 daratumumab 介导的细胞裂解率从 18.8% 升至 23.2%（p < 0.001），与血液中 CD3−CD56+CD16+ NK 细胞（增加 348%）、HLA-DR+CD14dimCD16+ 单核细胞（增加 125%）和 HLA-DR+CD14+CD32+ 单核细胞（增加 41%）频率升高有关（p < 0.01）。但总体而言，血液中的总浆细胞（CD38+CD138+）和克隆性浆细胞（CD38brightCD138+CD45−/dimCD19− 且轻链受限）均未增加（p > 0.05）。值得注意的是，表达 daratumumab 靶抗原 CD38 的 NK 细胞增加了 305%，这可能使 NK 细胞更易受到 daratumumab 介导的同类相残杀——即 NK 细胞对结合 daratumumab 的 NK 细胞启动 ADCC。总之，运动可小幅提高体外 daratumumab 介导的 ADCC 效力，但浆细胞基本未变，且血液中表达 daratumumab 靶抗原 CD38 的 NK 细胞增加。未来研究应考察骨髓瘤患者 daratumumab 治疗期间的最佳运动时机，以避免加重 daratumumab 介导的 NK 细胞裂解。
Multiple myeloma is a haematological cancer characterised by the accumulation of clonal plasma cells in the bone marrow and is commonly treated with daratumumab, an anti-CD38 monoclonal antibody immunotherapy. Daratumumab often fails to induce stringent complete responses, due in part to resistance to antibody-dependent cellular cytotoxicity (ADCC) exerted by natural killer (NK)-cells and monocytes. Exercise bouts undertaken by healthy people induce lymphocytosis in blood, including to NK-cells and B-cells, but the effects of exercise are unknown in myeloma patients. In addition, whether exercise mobilises plasma cells has not been adequately investigated, and as such the potential impact of exercise on daratumumab treatment is unclear. In this exploratory pilot study, n = 16 smouldering multiple myeloma participants enrolled and n = 9 completed the study which comprised a bout of cycling 15% above anaerobic threshold for 30-min, with blood samples collected pre-, immediately post-, and 30-min post-exercise. Peripheral blood mononuclear cells were isolated from blood samples and incubated with the RPMI-8226 plasmacytoma cell line, with or without the presence of daratumumab to determine specific lysis using a calcein-release assay. Daratumumab-mediated cell lysis increased from 18.8% to 23.2% pre- to post-exercise, respectively ( p < 0.001), owing to an increased frequency of CD3 - CD56 + CD16 + NK-cells (+348%), HLA-DR + CD14 dim CD16 + monocytes (+125%), and HLA-DR + CD14 + CD32 + monocytes (+41%) in blood ( p < 0.01). However, overall, total plasma cells (CD38 + CD138 + ) nor clonal plasma cells (CD38 bright CD138 + CD45 -/dim CD19 - with light-chain restriction) increased in blood ( p > 0.05). Notably, we observed a 305% increase in NK-cells expressing CD38, the daratumumab target antigen, which might render NK-cells more susceptible to daratumumab-mediated fratricide - whereby NK-cells initiate ADCC against daratumumab-bound NK-cells. In conclusion, exercise modestly improved the efficacy of daratumumab-mediated ADCC in vitro . However, plasma cells were largely unchanged, and NK-cells expressing CD38 - the daratumumab target antigen - increased in blood. Future research should consider the optimal timings of exercise during daratumumab treatment in myeloma to avert exacerbation of daratumumab-mediated NK-cell lysis.
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