Engineered T Cells Can Drive Custom Immune Cell Responses

Engineering T cells to recognize tumor antigens has had great success in some tumor types. However, the efficacy is limited by the endogenous T-cell response, and some aspects of the T-cell response can be deleterious. Further, T-cell therapies must overcome the immunosuppressive tumor microenvironment. In an effort to overcome these challenges, Roybal and colleagues used a customizable synthetic Notch (synNotch) modular receptor system in which an extracellular antigen receptor is linked to the Notch cleavage domain fused to an intracellular transcription factor. Binding of a specific tumor antigen to the synNotch receptor thus results in cleavage and release of the transcription factor and expression of a specific transcriptional program, thereby allowing a customized cellular output controlled by the transcription factor. For example, in response to the tumor antigen CD19, CD4⁺ and CD8⁺ T cells expressing synNotch were able to drive antigen-induced selective transcription of individual cytokines, demonstrating the potential value of synNotch in reducing unwanted cytokine expression and customizing the T-cell response. This system could also be used with the TBX21 transcription factor (also known as TBET) to drive CD4⁺ T cells to differentiate into antitumor T helper 1 (T_h1) cells instead of suppressive T_h2 cells and thus skew T-cell fate toward a potentially beneficial phenotype. Other potential applications of the synNotch system included targeted therapeutic delivery of the apoptosis-inducing TRAIL ligand and release of therapeutic antibodies including αPD1, αCTLA4, and bispecific T-cell engagers (BiTE). In vivo, in tumor xenografts the synNotch system could be used to effectively induce IL2 secretion, demonstrating the feasibility of this approach, and using synNotch to deliver the CD19/CD3 BiTE blinatumomab resulted in tumor clearance. Together, these findings demonstrate that the synNotch system can be used to customize the T-cell response to potentially remodel the tumor microenvironment and deliver therapeutic agents.

Roybal KT, Williams JZ, Morsut L, Rupp LJ, Kolinko I, Choe JH, et al. Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell 2016;167:419–32.e16.