Mechanistic modelling of tyrosine recombination reveals key parameters determining the performance of a CAR T cell switching circuit.

Inducible genetic switches based on tyrosine recombinase-based DNA excision are a promising platform for the regulation and control of chimeric antigen receptor (CAR) T cell activity in cancer immunotherapy. These switches exploit the increased stability of DNA excision in tyrosine recombinases through an inversion-excision circuit design. Here, the authors develop the first mechanistic mathematical model of switching dynamics in tyrosine recombinases and validate it against experimental data through both global optimisation and statistical approximation approaches.

Inducible Gene Switches with Memory in Human T Cells for Cellular Immunotherapy.

Cell-based therapies that employ engineered T cells-including those modified to express chimeric antigen receptors (CARs)-to target cancer cells have demonstrated promising responses in clinical trials. However, engineered T cell responses must be regulated to prevent severe side effects such as cytokine storms and off-target responses. Here we present a class of recombinase-based gene circuits that will enable inducible, one-time state switching in adoptive T cell therapy using an FDA-approved drug, creating a generalizable platform that can be used to control when and how strongly a gene is expressed.

Synthetic biology approaches in cancer immunotherapy, genetic network engineering, and genome editing.

Investigations into cells and their contents have provided evolving insight into the emergence of complex biological behaviors. Capitalizing on this knowledge, synthetic biology seeks to manipulate the cellular machinery towards novel purposes, extending discoveries from basic science to new applications. While these developments have demonstrated the potential of building with biological parts, the complexity of cells can pose numerous challenges.

Synthetic biology in cell-based cancer immunotherapy.

The adoptive transfer of genetically engineered T cells with cancer-targeting receptors has shown tremendous promise for eradicating tumors in clinical trials. This form of cellular immunotherapy presents a unique opportunity to incorporate advanced systems and synthetic biology approaches to create cancer therapeutics with novel functions. We first review the development of synthetic receptors, switches, and circuits to control the location, duration, and strength of T cell activity against tumors.

Identifying hubs in protein interaction networks.

Background: In spite of the scale-free degree distribution that characterizes most protein interaction networks (PINs), it is common to define an ad hoc degree scale that defines "hub" proteins having special topological and functional significance. This raises the concern that some conclusions on the functional significance of proteins based on network properties may not be robust.

Methodology: In this paper we present three objective methods to define hub proteins in PINs: one is a purely topological method and two others are based on gene expression and function.