Non-viral vectors for CAR-T cell therapy

Researchers of Fraunhofer Institute for Cell Therapy and Immunology have published a review of the current global research and development status of non-viral vectors for producing CAR-T cells in the Nature Reviews Methods Primers journal.

The approval of the first CAR cell therapeutics in 2017 (USA) and in 2018 (EU) has led to an innovative leap in cancer medicine and to a whole wave of new developments and studies.

CAR stands for Chimeric Antigen Receptor and, hence, in short, for a molecule which can recognise specific surface characteristics (antigens) on diseased cells, and then go on to activate T cells.

Since then, CAR-T cell therapies have yielded remarkable success rates in the treatment of haematological cancers. The effect is based on the genetic modification of the patient’s own immune cells. To achieve this, the T cells are isolated and equipped with the genetic blueprint for the chimeric antigen receptor which the cells then produce themselves and which are then presented on the surface of the cell.

In this context, the transport of the genetic material into the T cells constitutes a critical moment: This requires a vehicle, the so-called vectors, to introduce the required CAR genes into the cells. The methods approved so far exclusively use viral vectors, i.e. modified viruses, to achieve this. In this process, the natural characteristic of viruses (i.e. introducing genetic material into cells and integrating it into the genome of the T cells) is used. For the CAR-T cell therapy, these viruses are modified by removing all illness-causing genes and replacing them with therapeutic genes, i.e. the CAR.

This method for the genetic modification of T cells has proven to be highly effective so far; however, it is associated with a number of biological, logistic and financial challenges. Non-viral vectors for the genetic modification of immune cells offer properties to overcome these challenges and, for this reason, a range of research and development projects are focusing on these.

Together with international partners, researchers of the Fraunhofer Institute for Cell Therapy and Immunology have now summarised the current status of the research on the use of various non-viral vectors for CAR-T cell therapy for the first time and published the results in a review in Nature Reviews Methods Primers.

The article "Non-viral vectors for chimeric antigen receptor immunotherapy" provides an overview of the three most important non-viral vector systems (mRNA, transposons, and precise genome scissors). It discusses molecular biology methods, clinical results current challenges, as well as aspects of pharmaceutical production and translation.

For their article, the authors have analysed more than 250 publications and more than 150 clinical studies and summarised the most important results.

Fraunhofer IZI has long-standing experience in the development and production of CAR-T cell therapies. Non-viral methods for the genetic modification of cells are being investigated and used to generate CAR-T and CAR-NK cells at the institute. These efforts also involve molecular biology optimisation and process development work. 
 

Publication

Tretbar US, Rurik JG, Rustad EH, Sürün D, Köhl U, Olweus J, Buchholz F, Ivics Z, Fricke S & Blache U. Non-viral vectors for chimeric antigen receptor immunotherapy. Nat Rev Methods Primers 4, 74 (2024). https://doi.org/10.1038/s43586-024-00348-w
 

Partners

Karolinska Institutet, Stockholm, Sweden

Oslo University Hospital, Oslo, Norway

University Hospital Carl Gustav Carus, Dresden, Germany

Paul-Ehrlich-Institut (German Federal Institute for Vaccines and Biomedicines), Langen, Germany
 

Funding

The preparation of the publication was supported by the following programs:

BMBF-Clusters4Future »SaxoCell«

Fraunhofer Cluster of Excellence Immune Mediated Diseases (CIMD)

Fraunhofer funding program »International Cooperation and Networking« (ICON)