They can also be coupled with costimulatory domains, used for the regulation of interleukin secretion, or to prevent CAR exhaustion. For example, they can be used to switch CAR antigenic specificity, create logic gates, or produce local activation under heat or light. Moreover, they offer many additional capabilities. They make it possible to remotely control CAR lymphocytes after they have already been administered to the patient. Scientists have responded to these clinical challenges with molecular switches. In the case of hematological malignancies, dangerous complications such as cytokine release syndrome may occur. The reason for this is, among other things, the lack of tumor-specific antigens which, in therapy, threatens to cause a lethal attack of lymphocytes on healthy cells. However, despite the fact that CAR-T already offers not only hope for development, but measurable results in the treatment of hematological malignancies, CAR-T still cannot be safely applied to solid tumors. The success of CAR therapy would not have been possible without the many discoveries that preceded it, most notably, the Nobel Prize-winning breakthroughs in cellular immunity. Self-sufficient push-button devices may provide a new level of convenience for patients to control their cell-based therapies.Īmong the many oncology therapies, few have generated as much excitement as CAR-T. As proof of concept, we show that finger-pressure activation of the subcutaneous implant can restore normoglycemia in a mouse model of type 1 diabetes. Release is fine-tuned by varying the frequency and duration of finger-pressing stimulation. Pushing the button causes transient percutaneous deformation of the implant's embedded piezoelectric membrane, which produces sufficient low-voltage energy inside a semi-permeable platinum-coated cell chamber to mediate rapid release of a biopharmaceutical from engineered electro-sensitive human cells. Here, we describe a self-sufficient subcutaneous push button-controlled cellular implant powered simply by repeated gentle finger pressure exerted on the overlying skin. However, current optogenetic, magnetogenetic, or electrogenetic devices require sophisticated electronics, complex artificial intelligence-assisted software, and external energy supplies for power and control. Traceless physical cues are desirable for remote control of the in situ production and real-time dosing of biopharmaceuticals in cell-based therapies. Such high-level control validates NHRs as a versatile, engineerable platform for programming multi-drug-controlled responses. In combination with an antagonist, output levels are tunable by up to three simultaneously present small-molecule drugs. For responses activated to saturation by an agonist for the first LBD, we show that outputs can be boosted by an agonist targeting the second LBD. Starting from the VgEcR/RXR pair, we demonstrate that novel (multi-)drug regulation can be achieved by exchange of the ecdysone receptor (EcR) ligand binding domain (LBD) for other human NHR-derived LBDs. The nuclear hormone receptor (NHR) superfamily offers promising starting points for engineering multi-input-controlled responses to clinically approved drugs. For increased controllability, multi-input switches that integrate several cooperating and competing signals for the regulation of a shared output are of particular interest. Protein-based switches that respond to different inputs to regulate cellular outputs, such as gene expression, are central to synthetic biology.
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