Hacking T cells with synthetic circuits to program antitumor responses

Anticancer therapies based on T cells expressing engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs) have great translational potential and in fact have already yielded remarkable results in patients with hematological malignancies. However, engineered T cell therapies also have important limitations. For example, inappropriate hyperactivation of engineered T cells can cause dangerous toxic side effects, and the immunosuppressive microenvironment of solid tumors can block T cell–mediated tumor killing. Strategies to tailor both the precise signaling inputs that stimulate T cell activation, as well as the ways that cells translate these signals into output responses, have the potential to overcome these limitations. During the past year, researchers at the intersection of synthetic and T cell biology have begun to tackle these problems by creating, for example, T cells that are activated only in response to specific small molecules or combinations of antigens. Although these advances are refining the signaling inputs that result in engineered T cell activation, there is a critical need for technologies that can similarly control the outputs of this process. A team at the University of California, San Francisco has now developed strategies to do just that. By engineering primary human T cells with synthetic Notch (synNotch) receptors—which contain a core regulatory domain from the Notch receptor, flanked by a synthetic extracellular recognition domain (commonly a single-chain antibody) and a synthetic intracellular transcription domain—it is possible to program these cells to sense an antigen of interest, then respond through a transmembrane cleavage event that releases the intracellular domain to drive the expression of target genes regulated by a cognate cis -activating promoter. The authors demonstrate the development of synthetic, modular, and combinatorial response programs driven by antigen recognition, including responses involving the production of immunostimulatory and immunosuppressive cytokines and chemokines; the biasing of T cell differentiation through the expression of master transcriptional regulators; and the production of therapeutic payloads that include the apoptotic agonist TRAIL, checkpoint inhibitors targeting programmed cell death protein 1 and cytotoxic T lymphocyte antigen-4, the secreted adjuvant flagellin, a bispecific T cell engager (BiTE) molecule, and combinations thereof. Importantly, these payloads are released specifically in response to even small quantities of tumor antigen in vitro and in vivo and are strong enough to drive tumor clearance. This work adds to a growing suite of synthetic biological tools that have the potential to eventually enable highly precise, sculpted antitumor responses that overcome the safety and efficacy limitations of current engineered T cell therapies. In the future, we can expect further expansion of these concepts as well as preclinical and clinical testing of optimized therapeutic T cells. K. T. Roybal et al. , Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell 167 , 419–432 (2016). [[Abstract]][1] [1]: http://www.cell.com/cell/abstract/S0092-8674(16)31244-2