CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Immunomodulation of NK, NKT and B/T cell subtypes in relapsed/refractory multiple myeloma patients treated with pomalidomide along with velcade and dexamethasone and its association with improved progression-free survival.
Immunomodulation of NK, NKT and B/T cell subtypes in relapsed/refractory multiple myeloma patients treated with pomalidomide along with velcade and dexamethasone and its association with improved progression-free survival.
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免疫标志物数量的预后意义仅在 PVd 组中可见，而这些免疫标志物在 Vd 组中均未显示出预后价值。本研究表明了免疫调节效应的重要性以及将泊马度胺加入 Vd 治疗所带来的治疗获益。
多发性骨髓瘤（MM）患者表现出免疫系统失调，而化疗药物进一步削弱了免疫系统。虽然已发现cereblon调节剂，如pomalidomide和lenalidomide，能够改善免疫特征，但它们与其他治疗联合使用时的效果尚不清楚。
我们对来自CC4047-MM-007（OPTIMISMM，NCT01734928）研究的366份外周血样本进行了纵向队列的免疫分析。该研究追踪了接受Velcade + dexamethasone（Vd）或Vd联合pomalidomide（PVd）治疗的复发/难治性多发性骨髓瘤（RRMM）患者。使用多色流式细胞术在三个时间点对来自186名患者的366份血液样本进行了评估：筛选期、第1周期第8天和第3周期。
在NK和NKT细胞群体中，加入pomalidomide未显示抑制NK细胞的频率。当NK细胞上激活标志物如p46/NKG2D双阳性表达高于中位数时，PVd治疗的患者显示出显著更好的（p=0.05）无进展生存期（PFS）（额外15个月），相比NK细胞上p46/NKG2D表达低于中位数的患者。在周期1时CD158a/b表达低于中位数的PVd治疗患者表现出显著更好的PFS（超过18个月）。在B细胞亚型中，与筛选样本相比，PVd治疗在周期1和周期3的第8天显著增加了B1b细胞的丰度（p<0.05）并减少了Bregs（p<0.05）。在配对样本中评估的所有B细胞标志物中，周期1第8天MZB细胞的较高表达导致PVd治疗患者的PFS增强。在T细胞中，与筛选样本相比，pomalidomide治疗未降低CD8 T细胞的频率。PVd治疗使CD8 T细胞上OX-40的表面表达越高以及CD4 T细胞上PD-1和CD25的表达越低，导致PFS改善。
Multiple Myeloma (MM) patients exhibit dysregulated immune system, which is further weakened by chemotherapeutic agents. While cereblon-modulating agents, such as pomalidomide and lenalidomide, have been found to improve the immune profile, the efficacy of their impact in combination with other treatments is yet unknown.
We conducted an immune-profiling of a longitudinal cohort of 366 peripheral blood samples from the CC4047-MM-007 (OPTIMISMM, NCT01734928) study. This study followed relapsed/refractory Multiple Myeloma (RRMM) patients who were treated with Velcade + dexamethasone (Vd), or Vd with pomalidomide (PVd). 366 blood samples from 186 patients were evaluated using multi-color flow cytometry at 3 timepoints: screening, day 8 of cycle 1, and cycle 3.
Among NK and NKT cell populations, adding pomalidomide showed no inhibition in the frequency of NK cells. When expression of double positivity for activation markers like, p46/NKG2D, on NK cells was higher than the median, PVd treated patients showed significantly better (p=0.05) progression-free survival (PFS) (additional 15 months) than patients with lower than the median expression of p46/NKG2D on NK cells. PVd treated patients who expressed CD158a/b below the median at cycle 1 demonstrated a significantly better PFS (more than 18months). Among B cell subtypes, PVd treatment significantly increased the abundance of B1b cells (p<0.05) and decreased Bregs (p<0.05) at day 8 of both cycle 1 and cycle 3 when compared to screening samples. Of all the B cell-markers evaluated among paired samples, a higher expression of MZB cells at day 8 of cycle 1 has resulted in enhanced PFS in PVd treated patients. Within T cells, pomalidomide treatment did not decrease the frequency of CD8 T cells when compared with screening samples. The higher the surface expression of OX-40 on CD8 T cells and the lower the expression of PD-1 and CD25 on CD4 T cells by PVd treatment resulted in improved PFS.
The prognostic significance for the number of immune markers is only seen in the PVd arm and none of these immune markers exhibit prognostic values in the Vd arm. This study demonstrates the importance of the immunomodulatory effects and the therapeutic benefit of adding pomalidomide to Vd treatment.
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