30 April

Cellular immunotherapy tested in a 3D bone marrow model

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A team of researchers of the UMC Utrecht (departments of Orthopaedics and Haematology) and Catherine Robin, group leader at the Hubrecht Institute (KNAW), collaborated on the development of a 3D in vitro model of the bone marrow niche, for the culture of hematopoietic cells. Using this model, primary multiple myeloma cells could be cultured in vitro, enabling testing of a novel cellular immunotherapy. The findings are published in OncoImmunology.

Bone marrow niches are microenvironments within the bone marrow, essential in supporting hematopoiesis and hematologic malignancies such as multiple myeloma. The progression of multiple myeloma depends on signals and cell-cell interactions provided by the surrounding bone marrow niche. A 3D model of the bone marrow niche is needed to support the culture of primary multiple myeloma in vitro, as these cells cannot be cultured independently. Once established, such a model can be used for both fundamental and translational research.

3D bone marrow niche model

In this study, 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.

Cellular therapy testing

The 3D bone marrow niche model enabled in vitro 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 and exerting a killing response towards the primary myeloma. No differences were observed comparing allogeneic and autologous therapy. The supporting stromal microenvironment was unaffected in all conditions.

Future perspectives

The developed 3D model surpassed conventional 2D models in many aspects. The 3D model enabled analyses of individual cells and cell populations, specific homing, and both on- and off-target effects, preparing the ground for the clinical testing of TEGs. The 3D model also allows studying novel immunotherapies, therapy resistance mechanisms and possible side-effects for this incurable disease, within the context of the engineered BM niche. Another step for the developed model is to test its usability for the in vitro culture of hematopoietic stem and progenitor cells, that also dependent on the bone marrow niche for their self-renewal and differentiation.

Cellular immunotherapy on primary multiple myeloma expanded in a 3D bone marrow niche model
Maaike V. J. Braham, Monique C. Minnema, Tineke Aarts, Zsolt Sebestyen, Trudy Straetemans, Anna Vyborova, Jurgen Kuball, F. Cumhur Öner, Catherine Robin & Jacqueline Alblas.
OncoImmunology 2018, DOI: 10.1080/2162402X.2018.1434465