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Cellular Control: Synthetic Signaling and Motility Systems

 
2012 Progress Report – Executive Summary
 

Vision: Engineering Cells and Cell-Like Devices as Next Generation Therapeutic Agents

Our overall translational goal is to apply the synthetic biology approaches that our center has developed to improve cancer therapy.  We are focused on two platforms.  Our first focus is applying cellular engineering methods to improve cancer-directed adoptive immunotherapy.  T cells can be modified to attack tumor cells by expressing artificial chimeric antigen receptors (CARs) directed against tumor associated antigens.  These cell- based therapies, although in clinical trials, are still far from ideal with respect to on- vs. off-target effects.  We are using synthetic biology approaches to engineer the signaling pathways of native T cell responses and in 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, etc.), such that they show improved control, discrimination and activity against cancer vs. non-cancer cells. In the long term, we envision that the tools we develop to engineer T cell signaling will have utility across various therapeutic applications of adoptive immunotherapy and cell therapy, beyond cancer applications. A second goal is to develop and demonstrate the potential of microfluidic jetting derived vesicles as a platform for engineering smart anti-cancer therapeutics.  This new platform allows the rapid generation of vesicles containing complex combinations of molecular cargos and membrane proteins.  Our goal is to demonstrate how these vesicles can be a flexible cell delivery system for DNA, proteins, and combination cargos, such as oncolytic systems of plasmids and proteins.

Current Progress:

Primary experimental focus:

We have focused on achieving greater tumor targeting specificity and control of the T cell activation response for adoptive immunotherapy; apply synthetic signaling design concepts to in vitro testing systems and translate to in vivo animal models where cell tracking and potential therapeutic T cell responses toward tumors can be gauged.

Secondary experimental focus:

We are addressing the need for high-throughput production of synthetic vesicles for delivery of proteins and DNA, such as those containing tumor-killing plasmids.

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