How does synthetic biology help immunotherapy conquer cancer?

July 8, 2019 news / BIOON / - immunotherapy is to use patients' own immune system to attack their cancer, which has become a hot field of research and clinical development Although researchers have several methods for immunotherapy, this article will introduce how synthetic biology can improve and increase the immunotherapy Arsenal for cancer Car-t (car represents chimeric antigen receptor, T represents T cell) cell therapy is one of the main driving factors of cancer immunotherapy interest It's a cell-based approach that extracts T cells from patients and then transforms them to have specific receptors that help them recognize and attack cancer Chimeric antigen receptors work by fusing a target binding domain and an activation domain that recognize cancer, and the activation domain enables T cells to enter the mode of attacking cancer A large number of these modified cells are then grown in the laboratory and sent back to the patient The first car-t therapy was approved by FDA in 2017, and more drugs are in clinical trials Synthetic biology has the potential to provide tools for improving immunotherapy such as car-t cell therapy, so as to help more patients At present, car-t still has many potential challenges, including the toxicity of attacking non cancer cells, the diversity of cancer cells that can lead to "clone escape", the injection of the right dose of car-t into patients, T cell immunosuppression (shutdown) and T cell apoptosis (cell death) Receptor engineering new receptors can be used to detect different types of molecules, and to turn on some output functions of cells The more easily the receptor is designed, the more molecules there are that can be used as input to therapeutic cells One paper shows that they can synthesize Notch receptors using different recognition domains, and Notch receptors using different transcription factors and activation domains This means that researchers can decide what the receptor reacts to and what it turns on when it binds to the target Typical car TS only change the input of the receptor, but the receptor can exchange input or output, or both Having several independent receptors will make therapeutic cells more complex to respond to signals in the body Photo source: the genetic circuit of PLoS blogs signal processing is usually established by synthetic biologists, enabling cells to accept some input and calculate what to do In addition to single input activated cells, cells can also be designed to respond to multiple signals and make decisions based on their neighboring cells and environment An example of a published mammalian genetic circuit is "blade", which can construct 113 different circuits in embryonic kidney and Jurkat T cells The blind system uses recombinase to create logic gates and can also be combined with crispr-cas9 to regulate host cell genes Large pathways such as those demonstrated by blade can bind to synthetic receptors so that cells can make decisions based on the combination of signals they see Safety kill switch because toxicity may be a problem, so it is best to turn off the switch when there is a problem One of the possible toxicities of car-t is called "cytokine release syndrome", and especially severe cases are called "cytokine storm" When the immune system has a strong response, many inflammatory cytokines are released, causing mild to severe symptoms, including fever, headache, rash, tachycardia, hypotension and dyspnea Photo source: NCI synthetic biologists have studied many "switches" in different organisms By implanting drug-induced killer switch in T cells, killer switch can be applied to car-t cells, which will provide a way for medical team to kill modified cells in case of adverse side effects Researchers and companies are also looking for ways to shut down or kill T cells when they are not needed These switch changes can help ensure that additional safety measures are in place for car-t cell therapy There are many types of cancer, and there are many ways to avoid successful treatment It is hoped that mammalian synthetic biology can enhance the immune system against cancer by improving car-t or other methods, so as to add something to immunotherapy toolbox Reference materials: [1] synthetic biology approvals to improving immunology [2] Benjamin h Weinberg et al Large scale design of robust genetic circuits with multiple inputs and outputs for Marxist cells, Nature Biotechnology (2017) Doi: 10.1038/nbt.3805 [3] deboki chakravati et al Synthetic biology in cell-based cancer immunotherapy ， Trends in Biotechnology (2015) DOI： 10.1016/j.tibtech.2015.05.001 【4】Florian Lienert et al Synthetic biology in mammalian cells： next generation research tools and therapeutics， Nature Reviews Molecular Cell Biology (2014) DOI： 10.1038/nrm3738
【5】Matthew J Brenner et al Synthetic Biology： Immunotherapy by Design ， Annual Review of Biomedical Engineering (2018) DOI： 10.1146/annurev-bioeng-062117-121147