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From target selection to patient stratification:CRISPR screening in primaryT cells


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onventionally, CRISPR screening has used stable cell lines to study whole-genome drug-gene interac-


tions revealing, for example, drug resis- tance or drug sensitivity, identifying syn- thetic lethality targets or deciphering com- plex phenotypes. Although more physio- logically relevant, CRISPR screening of pri- mary cells, ie those taken directly frompeo- ple, such as T cells from blood donors has presented greater challenges when trying to maintain cell viability throughout the edit- ing, in vitro analysis and screening process. After several years of research, Horizon Discovery has developed a CRISPR screen- ing technique that overcomes these chal- lenges for primary T cells. We focused on primary cells with the aim


of developing CRISPR screens that could improve drug discovery outcomes. Studying cells that are closer to a patient’s own cells means that the screens have the potential to identify targets that could be more relevant to the clinic. By contrast, screens of continuously-cultured cancer cell lines that have mutated and adapted to grow in culture medium might give skewed results compared with healthy tissue. Advances in cell therapies that have now


made it into patients have also helped our work with primary T cells. As companies and researchers develop adoptive T cell and CAR-T cell therapies they have found ways to keep autologous and allogeneic cells alive in culture long enough for manipula- tion, expansion and delivery to the patient. With these technologies and techniques having enabled cell therapies to move from bench to bedside, they are now returning to the bench and being used in new applica- tions for in vitro screening. These primary T cell-based CRISPR


Drug DiscoveryWorld Summer 2019


screens will be useful in immuno-oncology, where pharma and biotech companies can use them to select candidates for develop- ment, for example identifying drugs that will stop the tumour microenvironment ‘switching off’ T cells, or ensuring that T cells survive and remain active for longer. Drug developers can also use the screens to assess their existing pipelines and verify the mechanism of action of molecules in pre- clinical and clinical studies. In January 2019, Horizon Discovery’s


Screening Unit extended its CRISPR screening service to include ex vivo T lym- phocytes for immunology-based research in drug discovery. In the future it may be possible to apply


similar approaches to other immune cells, such as B cells, macrophages and natural killer cells. As well as looking at mecha- nisms to up-regulate the immune system, these CRISPR screens may also reveal ways in which the immune system can be down-regulated, for example, in the devel- opment of treatments for autoimmune diseases.


DDW


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