Abstract 2887: Patient-derived 3-dimensional models of pediatric tumors for in situ study of cancer biology, immunotherapy, and drug treatment
Authors: Levings Padraic P. , Urueña Juan M. , McGhee Eric O. , McGhee Alex J. , Hood Derek L. , Meter Kylie E. Van , Ghivizzani Steve H. , Anderson Colin J. , Sawyer Wallace G. 
Published: August 2019

The 2D culture systems are currently the mainstay of pre-clinical testing of potential therapeutics, however, these models fail to recapitulate the dynamic and heterogenous conditions found within the in vivo tumor microenvironment and are poor predictors of clinical activity. Patient derived xenograft models of cancer excel recapitulating these complexities but are not the most tractable approaches for high throughput efficacy testing, particularly of immuno-oncologic therapies. In addition, small animal imaging techniques to noninvasively and longitudinally monitor PDX tumor growth require costly equipment and a high level of technical expertise. Thus, there is a tremendous need for in vitro model systems with improved diagnostic accuracy to better predict therapeutic responses earlier in drug development. This need is even more acute for pediatric cancers such as osteosarcoma (OS) and glioblastoma (GB), for which there are few or no viable non-clinical models to investigate basic science or for pre-clinical drug efficacy studies.We have developed a 3D culture system integrating 3D printing in Liquid Like Solids (LLS) materials to enable the precise arrangement of delicate and highly detailed assemblies of cells, that include, fibroblasts, vascular endothelial cells, and/or activated T-cells and extra-cellular matrix components-with a modular perfusion system that uses a negative pressure chamber to draw fluid through the culture chamber and assay workspace without disturbing the positioning of the experiments. Real-time imaging in these 3D assays is performed in situ using confocal microscopy under controlled perfusion. In this study we present preliminary results from in situ studies of drug cytotoxicity, angiogenesis, and fibroblast activation, as well as, T cell migration and infiltration in bio-fabricated patient derived 3D tumor microtissues of OS and GB. We assessed the impact of oxygen tension, DNA damage, ER stress, and stromal composition (matrix and cell types) on response to frontline therapies, tumor angiogenesis, and T cell activation. Secretion of cytokines, pro-inflammatory factors and the release of damage-associated molecular patterns by microtumor constructs cultured under each condition was measured by ELISA. These data highlight the unique capabilities of our integrated confocal microscope and 3D passive perfusion culture system for studies of cancer biology, immunotherapy, and drug treatment regimens to provide in situ measurements of tumor-stroma interactions and immune cell invasion dynamics in precision fabricated OS and GB patient derived 3D microtissues.

Citation Format: Padraic P. Levings, Juan M. Urueña, Eric O. McGhee, Alex J. McGhee, Derek L. Hood, Kylie E. Van Meter, Steve H. Ghivizzani, Colin J. Anderson, Wallace G. Sawyer. Patient-derived 3-dimensional models of pediatric tumors for in situ study of cancer biology, immunotherapy, and drug treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2887.