Preclinical and clinical development of a novel CAR-T cell therapy for the treatment of multiple myeloma and clear cell renal cell carcinoma

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CAR-T cell therapy is based on the principle of equipping immune cells (T cells) with an artificial chimeric antigen receptor (CAR) by genetic modification. This enables the immune cells to identify specific surface structures (antigens) on cancer or other target cells and to activate a corresponding immune response.

In the therapies approved to date, the T cells are modified using viral vectors and in most cases address the cell surface molecule CD19, which is expressed by the target cells in particular in certain types of blood cancer and lymphomas.

With the ROR2-CAR-T cell therapy, scientists at the University Hospital of Würzburg have developed an immunotherapy that differs from previously approved therapies both in the type of genetic modification and the target antigen addressed. This is now to be transferred to clinical application as part of a project funded by the German Federal Ministry of Education and Research.

The ROR2 protein is a transmembrane receptor that plays an important role especially during embryonic development. It is normally not expressed, or only very slightly expressed, in normal, healthy cells and tissues. However, in some cancers, including multiple myeloma and clear cell renal cell carcinoma, it is highly expressed on the cancer cells in question. This makes the antigen a suitable target for appropriately targeted CAR-T cells.

In this project, a new method for the production of autologous CAR-T cells, which is still being tested, is used. The genetic modification of the patient's own T cells is carried out via a non-viral gene transfer, which, compared to viral gene transfer, will enable a simpler, more scalable and thus less expensive production process. The chimeric antigen receptor was designed to initiate overexpression of the transcription factor Batf3 in addition to T cell activation to improve T cell persistence and tumoricidal activity.

Fraunhofer IZI is responsible for two main areas within the project. On the one hand, the preclinical testing of the safety and efficacy of the novel CAR-T cell product within the scope of a GLP study, and on the other hand, the pharmaceutical manufacturing of the investigational medicinal products for the clinical study, including the prior establishment and validation of the manufacturing process as well as the safety-relevant quality controls.

The multicenter clinical study (phase I, first-in-human) will be realized at the University Hospitals of Würzburg (coordination, Prof. Dr. M. Hudecek), Regensburg and Leipzig.