Braham Maaike V J, Minnema Monique C, Aarts Tineke, Sebestyen Zsolt, Straetemans Trudy, Vyborova Anna, Kuball Jurgen, Öner F Cumhur, Robin Catherine, Alblas Jacqueline
Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Hematology, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands.
Oncoimmunology. 2018 Feb 22;7(6):e1434465. doi: 10.1080/2162402X.2018.1434465. eCollection 2018.
Bone marrow niches support multiple myeloma, providing signals and cell-cell interactions essential for disease progression. A 3D bone marrow niche model was developed, in which supportive multipotent mesenchymal stromal cells and their osteogenic derivatives were co-cultured with endothelial progenitor cells. These co-cultured cells formed networks within the 3D culture, facilitating the survival and proliferation of primary CD138 myeloma cells for up to 28 days. During this culture, no genetic drift was observed within the genomic profile of the primary myeloma cells, indicating a stable outgrowth of the cultured CD138 population. The 3D bone marrow niche model enabled testing of a novel class of engineered immune cells, so called TEGs (αβT cells engineered to express a defined γδTCR) on primary myeloma cells. TEGs were engineered and tested from both healthy donors and myeloma patients. The added TEGs were capable of migrating through the 3D culture, exerting a killing response towards the primary myeloma cells in 6 out of 8 donor samples after both 24 and 48 hours. Such a killing response was not observed when adding mock transduced T cells. No differences were observed comparing allogeneic and autologous therapy. The supporting stromal microenvironment was unaffected in all conditions after 48 hours. When adding TEG therapy, the 3D model surpassed 2D models in many aspects by enabling analyses of specific homing, and both on- and off-target effects, preparing the ground for the clinical testing of TEGs. The model allows studying novel immunotherapies, therapy resistance mechanisms and possible side-effects for this incurable disease.
骨髓龛支持多发性骨髓瘤，提供疾病进展所必需的信号和细胞间相互作用。构建了一种三维骨髓龛模型，其中支持性多能间充质基质细胞及其成骨衍生物与内皮祖细胞共培养。这些共培养的细胞在三维培养物中形成网络，促进原发性CD138骨髓瘤细胞存活和增殖长达28天。在该培养过程中，原发性骨髓瘤细胞的基因组谱未观察到基因漂移，表明培养的CD138群体稳定生长。三维骨髓龛模型能够在原发性骨髓瘤细胞上测试一类新型的工程免疫细胞，即所谓的TEG（经工程改造表达特定γδTCR的αβT细胞）。从健康供体和骨髓瘤患者中获取细胞进行TEG的工程改造和测试。添加的TEG能够穿过三维培养物迁移，在24小时和48小时后，8个供体样本中有6个对原发性骨髓瘤细胞产生杀伤反应。添加 mock 转导的T细胞时未观察到这种杀伤反应。比较同种异体和自体治疗未观察到差异。48小时后，所有条件下支持性基质微环境均未受影响。添加TEG治疗时，三维模型在许多方面超越了二维模型，能够分析特异性归巢以及靶向和脱靶效应，为TEG的临床试验奠定了基础。该模型有助于研究针对这种不治之症的新型免疫疗法、治疗抵抗机制和可能的副作用。
