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Introduction: Three-dimensional (3D) collagen scaffold models, due to their ability to mimic the tissue and organ structure in vivo, have received increasing interest in drug discovery and toxicity evaluation. Methods: In this study, we developed a perfused 3D model and studied cellular response to cytotoxic drugs in comparison with traditional 2D cell cultures as evaluated by cancer drug cisplatin. Results: Cancer cells grown in perfused 3D environments showed increased levels of reactive oxygen species (ROS) production compared to the 2D culture. As determined by growth analysis, cells in the 3D culture, after forming a spheroid, were more resistant to the cancer drug cisplatin compared to that of the 2D cell culture. In addition, 3D culturing cells showed elevated level of ROS, indicating a physiological change or the formation of a microenvironment that resembles tumor cells in vivo. Conclusions: These data revealed that cellular response to drugs for cells growing in 3D environments are dramatically different from that of 2D cultured cells. Thus, the perfused 3D collagen scaffold model we report here might be a potentially very useful tool for drug analysis. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a common form of acute leukemia, and the currently available treatments are unsatisfactory. In the present study, we report an immune cell therapeutic strategy that employed genetically modified bifunctional CAR-NK cells. These cells combined the efficient targeting of AML cells by the CD33 molecule with the concomitant stimulation of NK cell-mediated cytotoxicity via the expression and extracellular secretion of anti-CD16 antibody (B16) that binds back to the FC receptor of NK cells. Compared to CAR-NK cells that target CD33 only, the bifunctional CD33/B16 CAR-NK cells showed superior killing efficiency toward AML cells in vitro. The increase in efficiency was approximately four-fold, as determined based on the number of cells needed to achieve 80% killing activity. An in vivo study using a xenograft model also revealed the effective clearance of leukemic cells and much longer survival, with no relapse or death for at least 60 days. In addition, the safety of CAR-NK cells did not change with additional expression of B16, as determined by the release of cytokines. These data revealed the development of a promising CAR-NK approach for the treatment of patients with AML, which may improve CAR-NK-based treatment strategy in general and may potentially be used to treat other tumors as well. • A CAR-NK based immune therapy strategy to treat AML by targeting CD33 with concomitant secretion of anti-CD16 antibody. • CD33/B16 CAR-NK cells showed 4-fold higher killing efficiency toward AML cells in vitro than targeting CD33 only. • In vivo study with xenograft model revealed effective clearance of leukemic cells and much longer survival. • This double-targeting approach has the potential to boost CAR-NK based therapy, which may also apply to combat other tumors. [ABSTRACT FROM AUTHOR]