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Optimizing CAR-T-cell therapy using 3D tumor models and real-time cell imaging
Conferences abstracts

Optimizing CAR-T-cell therapy using 3D tumor models and real-time cell imaging

Chimeric antigen receptor (CAR) T-cell therapy accounts for one of the most promising therapeutic advances in cancer immunotherapy. In this form of adoptive cell transfer, T-cells of a patient are engineered to express so-called ‘CARs’, in which the antigen-recognition capacity of antibodies is combined with T-cell activating domains. So far, CAR-T-cell therapy obtained its most impressive results in hematological malignancies resulting in the approval of five CAR-T cell products by the FDA for hematologic indications. However, CAR-T-cell therapy has not mirrored its success in solid tumors. The poor efficacy of CAR-T-cell therapy in solid tumors has, in part, been attributed to the lack of understanding in how CAR-T-cells function in a solid tumor microenvironment. Classical validation methods rely on the use of specificity and functionality assays in 2D models against adherent target cells or target cells in suspension. Yet, by using these models, observations made in vitro may differ greatly to an in vivo situation where tumors are engrafted in 3D structures. We developed a more relevant and translational 3D tumor model using eGFP+ target cells. This allows us to couple 3D tumor cell killing by CAR-T-cells to live-cell imaging, providing an efficient quantification of target cell death. As proof- of-concept, we used a 3D model of eGFP+ glioblastoma cells and CAR-T-cells targeting a pan-cancer antigen. This 3D glioblastoma model allowed us to show that classical scFv-based CAR-T-cell therapy of glioblastoma cells can be improved by nanoCAR-T-cells. Furthermore, combining nanoCAR-T-cell therapy with a genetic approach of nanobody-based anti-PD-L1 immune checkpoint blockade further increased the cytotoxicity of the nanoCAR-T-cell therapy.
03:255 months ago
Stem cell assays for animal-free developmental neurotoxicity assessment of compounds (video in Dutch)
Innovation examples
ToxicologyIn vitro

Stem cell assays for animal-free developmental neurotoxicity assessment of compounds (video in Dutch)

Victoria de Leeuw worked as a PhD candidate in the research group of prof. Aldert Piersma at the RIVM between 2016 and 2020. Piersma's lab studies the effects of compounds on development of the embryo during pregnancy with among others stem cell cultures. The project of Victoria was aimed to differentiate embryonic stem cells (of mouse and human origin) into neurons and astrocytes, which could mimic small parts of embryonic brain development. These models were able to show some of the known toxic mechanisms induced by these compounds, congruent with what they we hypothesised to mimic. Therefore, these two stem cell assays make a useful contribution to the animal-free assessment of developmental neurotoxicity potential of compounds. Onderzoeker: Victoria de Leeuw op het RIVM. Video: Sophie Koster Videoproducties
02:232 years ago
Zebrafish in toxicity testing
Innovation examples

Zebrafish in toxicity testing

Zebrafish are increasingly recognised as a useful model for toxicity testing of chemical substances. Testing strategies are becoming more based on mechanisms of toxicity structured in adverse outcome pathways describing the chain of events leading to toxicity or disease. Using a battery of dedicated in vitro and in silico assays, insight can be gained in how exposure leads to disease. For certain diseases it is known that toxicity relies on the interaction between different organs and cell types, which requires research on whole organisms in addition to simple in vitro models. The zebrafish is considered a valuable whole organism model in a mechanism-based testing strategy. At RIVM, the zebrafish embryo model is used for testing the effect of chemical substances on several adverse outcomes and diseases. For more information see: https://ehp.niehs.nih.gov/doi/10.1289/EHP9888; https://doi.org/10.3390/ijerph18136717; www.linkedin.com/in/harm-heusinkveld
03:014 days ago
Human pluripotent stem cell derived cardiomyocytes for disease modelling and drug discovery
Innovation examples
ToxicologyInnovationIn vitro

Human pluripotent stem cell derived cardiomyocytes for disease modelling and drug discovery

Berend van Meer did his PhD research in the research group of prof. Christine Mummery at the department of Anatomy and Embryology of the Leiden University Medical Center. In this group, human pluripotent stem cell derived (Organ-on-Chip) models are being developed, mostly cardiovascular models. The work of Berend aimed to understand how well these stem cell based cardiac models can predict the effect of (well-known) drug therapies in patients. Importantly, the outcomes of the experiments were compared to very similar measurements in rabbit heart muscle cells. And while animal models predicted less than 70% correctly, the human stem cell based models predicted almost 80% of the expected effects correctly. The research contributes to understanding the relevance of stem cell based models and strengthens the confidence regulators and pharmaceutical companies have in such models as animal alternatives in the drug development pipeline. Berend van Meer has won the Hugo van Poelgeest prize 2020 for his research on human pluripotent stem cell derived cardiomyocytes for disease modelling and drug discovery. Christine Mummery's lab on Heart on Chip, Disease modeling and toxicity: https://www.lumc.nl/org/anatomie-embryologie/research/902040935402533/
01:5613 months ago