Genetically engineered T-lymphocytes: drug synthesis at the patient's home
Researchers at the California Institute of Technology have demonstrated that a "switch" built into living T-lymphocytes of mice and humans, based on an RNA molecule, allows stimulating or suppressing the growth of these cells with a specific drug. In the future, scientists plan to use this technology to create drugs based on T-lymphocytes, the first versions of which are already undergoing clinical trials as a means to treat cancer and other diseases.
Researchers have been trying for a long time to find the possibility of using the immune system to destroy cancer cells that avoid immune recognition. One of the approaches is to isolate T-lymphocytes from the patient's blood – cells that form the body's response to specific pathogens – increasing their number and returning to the patient's bloodstream. Thanks to the achievements of genetic engineering, scientists have been able to modify these cells in order to increase their effectiveness. For example, currently clinical studies are undergoing a number of gene therapy approaches based on the use of modified cells carrying molecules that ensure their specific binding to tumor cells.
The tested methods have already demonstrated certain positive results, however, unlike natural T-lymphocytes, modified cells do not proliferate in the patient's bloodstream and remain in it only for a short time. This limits the ability of cells to mobilize other parts of the immune system to fight the disease. The administration of interleukin-2 to patients stimulates the proliferation and survival of T cells, however, in order to ensure the effective interaction of this cytokine with modified T lymphocytes, preliminary chemotherapy and/or radiotherapy that destroys natural T lymphocytes is required.
The authors have chosen a different approach to solving this problem. They embedded an RNA-based molecular switch into T-lymphocytes, developed in 2007 by Christina Smolke from Stanford University (California). This switch, created using synthetic biology methods, allows using a chemical compound to stimulate or suppress the expression of the desired gene.
The molecular switch used in the work contains an RNA sensor that reacts to the anti-asthmatic drug theophylline by triggering the synthesis of signaling molecules necessary for the proliferation of T-lymphocytes. The researchers injected mice with T cells containing such a molecular construct. After that, they added theophylline to the animal feed and demonstrated that the modified cells proliferate much faster.
The described approach also worked when using human T-lymphocytes. The results can be found in the article "Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems", published on April 26 in the preliminary on-line version of Proceedings of the National Academy of Sciences.
The use of a molecular switch based on RNA (and not protein) avoids another problem associated with the introduction of modified T-lymphocytes into the body – the development of an immune response against therapeutic cells. In addition, the development is an important achievement in the field of synthetic biology. Most of the molecular structures developed with the help of synthetic biology have been tested on microorganisms, mainly yeast and Escherichia coli (Escherichia coli). This work demonstrated that, at least, this design functions in human cells.
Another advantage of the molecular switch used is its modular structure. Researchers can change its components and, thus, create switches that trigger the synthesis of almost any molecules they need using various drugs. They plan to create molecular switches that react to inert molecules, such as vitamins.
Currently, the authors are modifying the system so that it can work with other officially approved drugs. They are also trying to embed a molecular switch into T-lymphocytes that specifically bind to tumor cells. Experts note that it is still far enough before the start of clinical testing of their proposed technology, since it is first necessary to prove its safety for animals and its ability to suppress tumor growth.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of TechnologyReview: Engineering Better Immune Cells.
11.05.2010