Abstract
Synthetic Biology has enabled new approaches to several medical applications including the development of immunotherapies based on bioengineered cells, and most notably the engineering of T-cells with tumor-targeting receptors, the Chimeric Antigen Receptor (CAR)-T cells. CAR-T-cells have successfully treated blood tumors such as large B-cell lymphoma and promise a new scenario of therapeutic interventions also for solid tumors. Learning the lesson from CAR-T cells, we can foster the reprogramming of T lymphocytes with enhanced survival and functional activity in depressing tumor microenvironment, or to challenge diseases such as infections, autoimmune and chronic inflammatory disorders. This review will focus on the most updated bioengineering approaches to increase control, and safety of T-cell activity and to immunomodulate the extracellular microenvironment to augment immune responses. We will also discuss on applications beyond cancer treatment with implications toward the understanding and cure of a broader range of diseases by means of mammalian cells engineering.
Highlights
Synthetic biology is suited for the development of safer immune-therapeutics by means of genetic reprogramming of immune cells (Kitada et al, 2018; Tokarew et al, 2018), or other mammalian cells to confer immune-mimetic characteristics (Liu et al, 2018)
This is further strengthened by the simultaneous binding of the co-receptor to MHC molecule on the surface of target cells
A third approach to achieve spatial and temporal control over engineered T-cells is the inducible Chimeric Antigen Receptor (CAR) system that consists of two incomplete CAR molecules that heterodimerize in presence of a small molecule which functions as a switch to activate T-cell response (Figure 1C; Wu et al, 2015)
Summary
Synthetic biology is suited for the development of safer immune-therapeutics by means of genetic reprogramming of immune cells (Kitada et al, 2018; Tokarew et al, 2018), or other mammalian cells to confer immune-mimetic characteristics (Liu et al, 2018). By implementing Boolean logic gates, genetic circuits integrate multiple extracellular and intracellular inputs, achieving sophisticated control of timing, localization, specificity, and strength of transgene expression, outsmarting classical cell engineering approaches typically based on ON-OFF switches. Patients with diffuse large B-cell lymphoma treated with Tisagenlecleucel, showed ORR in 53% and CRS in 58% of the cases (Schuster et al, 2017). Strategies to control T-cell activation are a major goal of synthetic biology
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