br Concluding Remarks Synthetic cytokine biology has become
Concluding Remarks Synthetic cytokine biology has become an important research area with novel solutions and ideas for therapeutic approaches, for example, synthekines, fusokines, immunocytokines, neoleukins, MESA receptors, or synthetic Notch or cytokine receptors. In addition to their huge impact on health and disease, the simple and recurrent principle of cytokine–receptor–kinase interaction and activation has laid the molecular basis for their great popularity and some current success stories in modern (immuno)-therapies. The construction of novel artificial switches in cytokine biology has been enabled by the general composition of cytokines and cytokine receptors, consisting of modular structures allowing a high degree of compatibility and exchangeability inside and outside of cytokine receptor families. As discussed in this review, many examples have shown that cytokines can be freely combined with fusion proteins to obtain cell-targeted applications or the assembly of nonnatural receptor complexes. With the approval of CAR T (-)-Huperzine A , the first synthetic biology genetic cellular therapy in humans, the perception of possibilities appears limitless. The procedure to generate patient-specific transgenic T cells from a patient’s own cells is, however, still challenging, time-consuming, and costly . In the future, these procedures might be simplified (e.g., automation, off-the-shelf immune cells with reduced antigenic potential) and allow the introduction of additional regulatory receptor systems in single cells 106, 107. Also, synthetic cytokines might not even be administered as biologicals in all cases, but be produced by other transgenic cells vital to the interaction with other engineered cells or with other somatic cell populations or tumor cells. Thus, these efforts may result in engineered personalized tumor microenvironments to enable optimal tumor defense. Engineered cytokine/cytokine receptor systems are also important beyond CAR T cells. These could be used in tumor-infiltrating lymphocyte (TIL) therapies and engineered TCR T cell therapies as well as in other cell types such as macrophages, NK cells, and dendritic cells within the realm of tumor-infiltrating immune cells. Just as certain cytokines and cytokine derivatives have made their way into the clinic as discussed here, more sophisticated cytokine fusion proteins/nanoparticles might be clinically approved. Fully synthetic cytokine/cytokine receptor systems 96, 100, 102, which might also be combined with protein circuits of endogenous protein inputs or optogenetics (Box 2) may open up completely new possibilities for improving immunotherapies but also potentially aid in diagnostics and therapies that use sensor cells or drug releaser cells 97, 108. Because neither ligands nor receptors require naturally occurring binding structures in vivo, they may allow cell-targeted activation without the need to consider activation of any other receptor or cell of an organism. For patient applications this might be considered as free from off-target effects, and likely used to reduce side effects. In this scenario, one concern might only be the toxic side effects that occur because of the activation of the modified transgenic cell by the synthetic cytokine/cytokine receptor system. As described here, synthetic ligand-based ligands such as GFP may be immunogenic  and trigger the production of neutralizing antibodies or cytotoxic effects. Thus, overcoming these limitations will be one major task, which may be possible using nonimmunogenic synthetic ligands as has recently been suggested for neoleukins. Taken together, although many questions remain (see Outstanding Questions), accumulating molecular and structural evidence is improving our understanding and informing putative future designs of agonistic and antagonistic cytokine intervention strategies in human diseases.
Acknowledgments This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB974 and SFB 1116).