3D tissue models for preclinical testing of augmented CAR T cells
T cells have been identified as one of the main defense lines of the immune system against tumors. The scientific break throughs of the recent years with immunologic checkpoint inhibitors and adoptive T-cell therapy are offering novel treatment options when the body defense mechanisms fail and T cells become dysfunctional. T cells expressing a chimeric antigen receptor (CAR) are one of the recent advancements and combine the specificity of an antibody to target-specific antigens on tumor cells with the ability of T cells to kill tumor cells.
CAR T cells have shown remarkable effects in the treatment of late stage lymphoma patients. Unfortunately, CAR T cell therapy for solid tumors has not been nearly as successful and further research is needed to improve the existing treatment options. However, current used test systems for CAR T cells such as conventional 2D tumor cell cultures and murine xenograft models lack important features of human tumors in vivo.
In this project we want to establish novel test systems for the development and preclinical testing of CAR T cells that closer resemble the situation in the patient. For this we will employ iPSC derived organoids that will be generated in close collaboration with the BIH Core Facility Stem Cells as well as patient derived organoids. Introduction of fluorescent reporters will allow high throughput screening of CAR-T cell induced toxicity using the confocal high content imaging platform at the BCRT. The focus will be on generating a model for lung-cancer using overexpression of the epidermal growth factor receptor (EGFR), a very common tumor associated antigen with tumorigenic potential. Once the organoid models are established, we can test the different CAR T cell products that are currently used and further developed in the institute. Next to the direct tumoricidal activity, also homing and invasion in the established tissue models as well as the capacity of CAR T cells to initiate durable responses will be studied in static and microfluidic systems.
1. Stark R. et al. (2018). Tissue-resident T cell maintenance is regulated by tissue damage via P2RX7. Science Immunology. 3(30: eaau1022
2. Ehlen L. et al. (2020). Novel methods for in vitro modeling of pancreatic cancer reveal important aspects for successful primary cell culture. BMC Cancer. 20(1) :417