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Cellular Control: Synthetic Signaling and Motility Systems

 

PI: Wendell Lim, Ph.D., University of California, San Francisco

The overall translational goal of this center is to apply synthetic biology approaches to improve cancer therapy.

BACKGROUND

Synthetic biology combines principles of engineering and biology to create new biological systems. The long-term goal of this center is to engineer cells and artificial cell-like devices that can be programmed to carry out specific diagnostic and therapeutic tasks. To this end, the center sought to understand the molecular signaling systems and motility machinery that allow cells to move in response to chemical signals. For example, they engineered G-protein coupled receptors (GPCRs) to cause white blood cells (neutrophils) to move toward novel stimuli. To control cell signaling responses, they developed a computational method for design of synthetic orthogonal protein pairs. They have used bacterial virulence proteins to artificially alter cell signaling in yeast cells and mammalian immune cells, showing that they can tune T cell response and temporarily prevent T cell activation. Engineering cells in such ways, the researchers aim to improve cancer-directed adoptive immunotherapy by increasing the effectiveness and safety of treatment.

TRANSLATIONAL GOALS

T cells can be modified to attack tumor cells by expressing artificial chimeric antigen receptors (CARs) directed against tumor-associated proteins. Such cell-based therapies, although in clinical trials, are still far from ideal with respect to on- vs. off-target effects and also in the ability to control designed responses. This center synthesizes biological devices to manipulate the signaling pathways of native T cells and CAR-expressing T cells, in order to tune and optimize their response behaviors (reducing basal signaling, increasing threshold of activation, improved in vivo localization/persistence, engineering pharmacological gating of responses, etc.), such that they show improved control, discrimination and activity against cancer vs. non-cancer cells. In the long term, the investigators envision that the tools they develop to engineer T cell signaling will have utility across various therapeutic applications of adoptive immunotherapy and cell therapy, beyond cancer applications. Next steps involve completing studies of their synthetic systems in relevant mouse models of cancer.

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