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

03:252 years ago

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.

Related

Cells4Thought: using iPSCs for neurodevelopmental health
Projects and initiatives
HealthToxicologyInnovationIn vitro

Cells4Thought: using iPSCs for neurodevelopmental health

The prevalence of neurodevelopmental disorders (NDDs), including cognitive impairments, is increasing worldwide with great impact on daily life quality. There is evidence that exposure to chemicals may contribute to the incidence of NDD. However, a causal link is lacking. Towards this goal, a human-relevant in vitro model system mimicking parts of brain development, such as neuronal network functioning, could be used for mechanistic research on how gene-environment interactions contribute to the development of NDD. This is going to be studied in the project Cells4Thought, using induced pluripotent stem cells form different individuals to study the effect of chemicals on neuronal differentiation.
02:3819 days ago
We all want a safer world for humanity, animals and the environment: Transition Animal-free Innovation
Projects and initiatives
HealthInnovationPolicy

We all want a safer world for humanity, animals and the environment: Transition Animal-free Innovation

Why is the transition to animal-free research so important? What are animal-free models? How does TPI (Transition Animal-Free Innovation) encourage their development and use? And who are we working with to make this happen? We explain this in our animation. More and more animal-free tests and research methods are becoming available, but not all research questions or safety tests can be answered in this way yet. In addition, the validation, qualification and acceptance of non-animal innovations still lags behind. Therefore, the Dutch Ministry of Agriculture, Nature and Food Quality (LNV) stimulates the development and application of animal-free innovations. This is done with the partner programme Transition Animal-free Innovation (TPI).
02:4855 days ago
New approaches for cancer hazard assessment
Innovation examples

New approaches for cancer hazard assessment

Chemical substances are subjected to assessment of genotoxic and carcinogenic effects before being marketed to protect man and the environment from health risks. For cancer hazard assessment, the long-term rodent carcinogenicity study is the current mainstay for the detection of nongenotoxic carcinogens. However, carcinogenicity studies are shown to have prominent weaknesses and are subject to ethical and scientific debate. A transition toward a mechanism-based weight of evidence approach is considered a requirement to enhance the prediction of carcinogenic potential for chemicals. At RIVM, we are working on this alternative approach for cancer hazard assessment, which makes optimal use of innovative (computational) tools and be less animal demanding. For more information, click on the link in the video or read on here (https://doi.org/10.1080/10408444.2020.1841732) and here (https://doi.org/10.1080/10408444.2018.1458818). Contact the expert (https://nl.linkedin.com/in/mirjamluijten)
03:142 months ago
Helpathon #10 – Can you help Jolanda and Elza?
Meeting videos
HelpathonsEducation

Helpathon #10 – Can you help Jolanda and Elza?

Jolanda van der Velden, Chair of Physiology, and Elza van Deel, Educator, from Amsterdam University Medical Center want to support PhDs in preparing for the animal-free transition. They are both looking for an implementation strategy and course design. Do you have an interest in animal-free education and education about animal-free research? Read more and register here (https://www.helpathonhotel.org/coming-up).
00:552 months ago