Synthetic biology approaches to engineer T cells

Abstract

There is rapidly growing interest in learning how to engineer immune cells, such as T lymphocytes, because of the potential of these engineered cells to be used for therapeutic applications such as the recognition and killing of cancer cells. At the same time, our knowhow and capability to logically engineer cellular behavior is growing rapidly with the development of synthetic biology. Here we describe how synthetic biology approaches are being used to rationally alter the behavior of T cells to optimize them for therapeutic functions. We also describe future developments that will be important in order to construct safe and precise T cell therapeutics.

Fig. 1. Engineering T cells for diverse clinical needs

a, Overview of adoptive immunotherapy using genetically modified T cells. b, Current and future applications for engineered T cells.

Fig. 2. Diverse synthetic modules have been developed to reprogram therapeutic T cells

a, Synthetic receptor designs for targeting disease antigens. ITAM: immunoreceptor tyrosine-based activation motif, scFv: single chain variable fragment. b, Methods for engineering T cells resistant to immunosuppressive microenvironments. ITIM: immunoreceptor tyrosine-based inhibitory motif, ITSM: immunoreceptor tyrosine-based switch motif. c, Approaches to engineer migration/trafficking control. d, Engineering safety switches and gated activation in gene modified T cells.

Fig. 3. Looking forward: design principles for next generation therapeutic T cells

a, Desirable overall clinical properties for next generation therapeutic T cells. b, Cellular activities to be independently controlled by user for enhanced therapeutic cell safety and precision. c, Multi-input systems required for complex Boolean logic and sophisticated decision making. d, Enhanced ligand/antigen density discrimination to distinguish normal vs disease target cells via tuning dose responses in engineered T cells. e, Engineered control of T cell response duration and state-switching.