Accelerated courses for CAR-T cells
Immunologists and oncologists use the body's immune system to fight cancer and other diseases using the technique of adoptive cell transfer. During a normal immune response, T-lymphocytes are trained by antigen-presenting cells (APC), thus maintaining a sufficient number of them in the body. The procedure of adoptive cell transfer simulates this process outside the human body: T-lymphocytes are taken from a blood sample, they are genetically modified and increased in the laboratory, and then injected into the patient's blood so that, for example, they recognize and destroy cancer cells. The procedure for creating a large batch of T-lymphocytes sufficient for therapeutic effect usually takes several weeks.
A research team led by David Mooney from the Wyss Institute at Harvard University has presented an alternative accelerated method for modifying T-lymphocytes. Using an APC-like biological culture, the researchers obtained a larger population of T-lymphocytes than with the currently used method, in an experiment with blood samples from mice and humans. They demonstrated the effectiveness of the new approach in mouse models with lymphoma treated with T-lymphocytes producing a chimeric antigen receptor (CAR-T cells).
The new approach in laboratory conditions simulates the learning process of T-lymphocytes occurring in the human body, when the APC, with the help of stimulating signals, induces the production of soluble factors on the membrane surface of primary T cells that increase their survival. As a result, learning and an increase in the number of T-lymphocytes occurs much faster.
By changing the composition of lipids, signaling and diffusion factors, a universal and flexible platform has been developed that can be used to enhance specific T-lymphocytes from a patient's blood sample and used to modernize existing methods of T-cell immunotherapy.
To develop an APC-like platform, the researchers combined the smallest medium-porous sticks of silicon oxide with interleukin-2 (IL-2). In the body, IL-2 is synthesized by APC and increases the survival of T cells. Silicon oxide sticks with IL-2 were coated with lipids to create a thin lipid bilayer similar to the cell membrane of the APC. The lipid bilayer was used by researchers to bind to receptors on the surface of T-lymphocytes. The three-dimensional platform was created by randomly stacking silicon sticks, the resulting pores were large enough for T cells to pass through them.
On the left: a raster electron micrograph of a platform consisting of a large number of small medium-porous silicon oxide sticks before coating with a lipid bilayer. On the right: T cells (blue) associated with an APC-like platform (brown). Here they divide and accumulate. Source: The Wyss Institute of Harvard University.
In a series of comparative experiments, the researchers demonstrated the advantages of an APC-like platform compared to currently used methods of adoptive cell transfer. A single use of the APC-like platform led to an increase in the initial number of mouse and human T-lymphocytes, 2-10 times greater than the currently used method. Another advantage of the new method is the ability to configure subpopulations of T-lymphocytes for specific purposes. This can be used in the future to improve their functionality.
To confirm the results obtained, a study was conducted on mouse models with lymphoma. The currently actively developing area of CAR-T lymphoma treatment with lymphocytes can be upgraded with the help of an APC-like platform: its use has made it possible to create a larger number of modified CAR-T cells. The resulting cells were as effective as the cells modified by the currently used method.
The researchers also paid attention to the use of an APC-like platform for modifying a complex of different clones of antigen-specific T cells. Such clones are constantly formed in the body to recognize small peptides that are part of foreign proteins.
The ability to modify rare subpopulations of T-lymphocytes will improve the accuracy of immunotherapy and reduce the number of side effects in a particular patient. This is a promising step towards the development of personalized medicine.
Article by Alexander S Cheung et al. Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells is published in the journal Nature Biotechnology.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Wyss Institute: Fast-tracking T cell therapies with immune-mimicking biomaterials.