The graft is not against the host

The idea of using genetically modified immune cells against infections and tumors is not new and has existed since the 1980s, but modified T cells are not as effective as naturally produced ones and have rather limited clinical value. With the help of CRISPR-Cas9 technology, scientists from the Munich University of Technology managed to make T-cells similar to those produced in the body.

There are two forms of T-cell therapy: either the recipient receives cells from a donor, or the recipient's own T-cells are removed, genetically reprogrammed in the laboratory and used against infections or tumors. The first method has shown its effectiveness during clinical trials, but reprogramming of immune cells is still fraught with a number of problems.

Modification of T-cell receptors

To obtain T-cells identical to natural ones, scientists used the CRISPR-Cas9 system, which works on the principle of scissors, cutting out and replacing target segments of the genome. Both the traditional and the newly developed method target receptors on the surface of T cells. They recognize specific antigens associated with pathogens or tumor cells that will be affected by the T cell. Each receptor consists of two molecular chains that are connected to each other. The genetic information of these chains can be modified to produce new receptors capable of recognizing any desired antigen. This is the essence of reprogramming T cells.

Data exchange using CRISPR-Cas9

The problem with traditional immunotherapy methods is that genetic information for new receptors is inserted into the genome randomly. This means that T cells are produced with both new and old receptors, or with receptors having one old and one new chain. As a result, T cells do not function as efficiently as naturally produced ones, and are also controlled differently. In addition, mixed chains can cause dangerous side effects (for example, a graft-versus-host reaction).

Using the CRISPR-Cas9 method, scientists completely replaced natural receptors with new ones, inserting them into the right place in the genome. In addition, the information for both chains has been replaced to avoid the formation of mixed receptors.

Natural properties

The advantage of genetically modified T cells is that they are controlled like physiological cells and have the same structure, but at the same time they are genetically modified.

Another advantage is that the new method allows you to change several T-cells at the same time and use them in combination so that they can recognize different targets. This is especially interesting for cancer treatment because tumors are very heterogeneous.

In the future, scientists plan to investigate new cells and their properties and conduct preclinical tests on mice, which is an important step in preparing for clinical trials in humans.

Article by Schober et al. Orthotopic replacement of T-cell receptor α- and β-chains with preservation of near-physiological T-cell function is published in the journal Nature Biomedical Engineering.

Elena Panasyuk, portal "Eternal youth" http://vechnayamolodost.ru / based on the materials of the Technical University of Munich: Successful T cell engineering with gene scissors.