Computational Design Used to Develop Synthetic Receptors to Enhance T Cell Therapy

Immunotherapy using bioengineered T cells, particularly chimeric antigen receptor T (CAR-T) cells, has shown success in treating blood cancers but faces challenges in solid tumors like breast, lung, and prostate cancers. A research team led by Patrick Barth at EPFL and Caroline Arber at UNIL-CHUV, has addressed these challenges by developing a computational platform to design synthetic protein receptors. Aiming to overcome the suppressive tumor microenvironment (TME), the team engineered receptors called T-SenSERs (tumor microenvironment-sensing switch receptors) that detect tumor-associated soluble signals and convert them into signals enhancing T cell activity when combined with conventional CAR-T cells.

The study, published in Nature Biomedical Engineering, describes how these modular receptors are assembled by combining distinct protein domains, including an external binding domain targeting tumor signals, a transmembrane region transmitting signals into the cell, and an internal domain that activates useful T cell functions. Barth notes, “What sets this approach apart from current protein design approaches is that it doesn’t treat proteins as rigid structures. Instead, it models them as dynamic, shape-shifting machines—allowing researchers to see, for the first time, how signals travel through these synthetic receptors to control cell behavior.”

Utilizing this platform, the team developed two receptor families responding to VEGF, a tumor-associated protein promoting blood vessel growth, and CSF1, which modulates immune cell behavior in tumors. Testing revealed that T cells bearing both CAR and T-SenSER receptors exhibited stronger and ligand-specific responses to tumors compared to CAR-T cells alone. The VEGF-sensing receptor (VMR) became active only in the presence of VEGF, while the CSF1-sensing receptor (CMR) provided a baseline activation enhanced by CSF1 presence. In mouse models of lung cancer and multiple myeloma, these engineered T cells demonstrated improved tumor control and longer survival.

Importantly, the approach allows tuning receptor behavior from always-on to strictly ligand-dependent or intermediate activation modes. Barth states, “This study represents the first demonstration of the computational design of single-pass, multi-domain receptors with programmable signaling functions and paves the way for the accelerated development of synthetic biosensors with custom-built sensing and response capabilities for basic and translational cell engineering applications.”