Research Objective: Cellular engineering to enhance T cell robustness and efficacy using metabolic reprogramming

Technology Outcome: Genetic, culture, and small molecule metabolic reprogramming tools.

The goal of TR&D 3 is to innovate cell engineering approaches based on genetic, tissue culture media, and small molecule inhibitors to metabolically reprogram immune cells to maximize function and persistence. Successful engineering of immune cells will entail modulation, programming, and even reprogramming of energy and substrate deriving metabolism. The Specific Aims of TR&D 3 are:

• Specific Aim 1: Employing synthetic biology, genetically egineer cells with enhanced mTORC1 activity by knocking down/out/mutating TSC2, leading to enhanced effector function characterized by more robust glycolytic reprogramming.
• Specific Aim 2: By regulating glutamine metabolism, formulate growth and differentiation conditions that promote the generation of cells epigenetically programmed to persist when adoptively transferred in vivo and to maximally respond upon rechallenge.
• Specific Aim 3: Based on novel findings regarding the ability of SGK1 to promote both a memory and effector T cell phenotype, develop small molecule inhibitors of SGK1 that can metabolically reprogram T cells both ex vivo and in vivo.

The studies outlined in these three Aims will provide a toolbox (genetic engineering, culture media, and small molecule inhibitors) for metabolic reprogramming that can be exploited to enhance cellular therapy for a vast array of immunologically engineered systems.