cell therapeutics

Cell and gene therapies are innovative treatment methods that enable curative approaches for severe, previously incurable diseases. In addition to hematopoietic stem cell transplants, therapies with genetically modified cells have also been approved in the United States and Europe in recent years as advanced therapy medicinal products (ATMPs). These CAR-T cell therapies, in which the patient's own T cells are modified with chimeric antigen receptors (CAR), have so far been used almost exclusively in cancer therapy.

CAR-T cell therapy

Approved CAR-T cell therapeutics, like the vast majority of new CAR-T cells in development, are based on the stable genetic modification of a patient's own cells using viral vectors. Since CAR-T cell therapy is a very young method, the long-term consequences of off-target effects, for example, have not been sufficiently investigated. Furthermore, persistent CAR-T cells can cause severe side effects. An alternative to stable modification is the temporary modification of cells using a messenger RNA (mRNA) that codes for the CAR protein.

The transfer of the CAR-T cell therapy approach to infectious diseases, autoimmune diseases and fibrosis is the current status of research. In fibrotic diseases, the stroma-immune cell axis plays a crucial role. Therefore, activated, misdirected fibroblasts represent an important target for therapies. In preclinical studies, stably generated CAR-T cells against activated fibroblasts have been successfully used to reduce fibrosis.

Treatment of immune-mediated diseases with CAR-T cell therapeutics

The goal is to develop transient CAR cell therapeutics for the treatment of immune-mediated diseases. To this end, new mRNA techniques and nanocarrier systems are being developed. In an establishment project, CAR T cells will be generated against activated fibroblasts using these methods. Human 3D cell culture and tissue models of fibrosis and a novel imaging platform will be used to test their function. A further goal is to transfer the technology to natural killer (NK) cells in order to develop donor-independent CAR cell therapies.

How will this development contribute to improving the status quo?

On the competence platform, mRNA-based CAR-T cell therapeutics are being developed that have an increased safety profile. This will create a transient ATMP approach for the treatment of fibrotic diseases. In order to meet the future demand for CAR cell therapies, the transition from autologous (patient's own) to allogeneic (donor-unrelated) products is being promoted so that as many patients as possible can be treated with a single product batch.

Combining complementary expertise

The Fraunhofer IZI heads the competence platform and the molecular biological ATMP development. The platform is supported by the Fraunhofer IAP-CAN with its expertise in the section of customized nanotransporter systems and by the Fraunhofer ITEM with its expertise in RNA therapeutics, in silico analytics and human in vitro and ex vivo fibrosis models.  For ATMP function testing, IZI and the Fraunhofer ISC (TLZ-RT) combine their expertise in cell analysis in the field of 3D cell culture and tissue models as alternatives to animal testing.

Outlook

The competence platform is designed to enable the Fraunhofer-Gesellschaft to compete internationally in the field of cell therapeutics for immune-mediated diseases. If the establishment project is successful, further ex vivo models of fibrotic tissue will be used to test the CAR cells in collaboration with the Fraunhofer ITEM. At the same time, the platform will be expanded in the medium term to include other cell therapy approaches (e.g. T-cell receptor-modified cells) and other target indications (e.g. osteoarthritis).