High-throughput T cell receptor engineering by functional screening identifies candidates with enhanced potency and specificity.

A major challenge in adoptive T cell immunotherapy is the discovery of natural T cell receptors (TCRs) with high activity and specificity to tumor antigens. Engineering synthetic TCRs for increased tumor antigen recognition is complicated by the risk of introducing cross-reactivity and by the poor correlation that can exist between binding affinity and activity of TCRs in response to antigen (peptide-MHC). Here, we developed TCR-Engine, a method combining genome editing, computational design, and deep sequencing to engineer the functional activity and specificity of TCRs on the surface of a human T cell line at high throughput. We applied TCR-Engine to successfully engineer synthetic TCRs for increased potency and specificity to a clinically relevant tumor-associated antigen (MAGE-A3) and validated their translational potential through multiple in vitro and in vivo assessments of safety and efficacy. Thus, TCR-Engine represents a valuable technology for engineering of safe and potent synthetic TCRs for immunotherapy applications.

The case for investing in the prevention and control of non-communicable diseases in the six countries of the Gulf Cooperation Council: an economic evaluation.

BACKGROUND: While the non-communicable disease (NCD) burden in the countries of the Gulf Cooperation Council (GCC) (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates) has surged over the past decades, the costs and return on investment (ROI) of implementing cost-effective, WHO-recommended NCD interventions have not been established. METHODS: We performed an economic analysis to estimate the ROI from scaling up four sets of NCD interventions over 15 years. We estimated the direct costs of the four main NCDs (cancer, diabetes, cardiovascular diseases and chronic respiratory diseases) using a prevalence-based, bottom-up cost-of-illness approach. We estimated indirect costs based on productivity loss due to absenteeism, presenteeism and premature deaths. We costed the scaling up of interventions using the WHO Costing Tool and assessed the health impact of interventions using the OneHealth Tool. We calculated ROI by comparing productivity and social benefits with the total costs of implementing the interventions. RESULTS: The four main NCDs cost the GCC economy nearly US$50 billion in 2019, equal to 3.3% of its gross domestic product. The indirect costs are estimated at US$20 billion or 40% of the total burden. Implementing the four modelled intervention packages in the six GCC countries over 15 years will cost US$14 billion, with an ROI of US$4.9 for every US$1 invested and significant health and social benefits, including 290 000 averted premature deaths. CONCLUSION: Based on the results of these six investment cases, we recommend actions to scale up current WHO-recommended cost-effective interventions, strengthen whole-of-government action, drive the NCD legislative agenda, build out the evidence base, generate additional advocacy material, and increase regional collaboration and data-sharing to establish best practices and monitor impact.