GMP Cell and Gene Therapy

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.

The establishment of a Good Manufacturing Practice (GMP)-compliant manufacturing process for the ROR2-CAR-T cells including qualification of all suppliers and equipment is performed at Fraunhofer IZI (Department GMP Cell and Gene Therapy). This also includes the validation of the manufacturing process on the basis of three process validation batches, the validation of all safety-relevant quality control methods (testing for sterility, testing for bacterial endotoxins, testing for mycoplasmas, determination of the "Vector Copy Number"), the aseptic process simulation (APS) as well as the update of the assortment list of the existing general manufacturing authorization for advanced therapy medicinal products according to §13 of the German Drug Law.

In the context of the planned clinical trial, Fraunhofer IZI acts as the central manufacturing site. All investigational medicinal products will be produced in the institute's clean rooms and tested for their quality parameters in the quality control laboratories as part of in-process and end-product controls. After approval by the Fraunhofer IZI's experts, the investigational medicinal products are delivered to the participating study centers for the treatment of patients.

The “MesemCart” product developed by BIONCaRT GmbH (formerly BioPlanta GmbH) is based on mesenchymal stromal cells and will be used to treat acute and chronic cartilage damage in the knee joint. The cells harvested from umbilical cord blood activate regenerative processes and help to restore hyaline cartilage. This novel treatment aims to repair the cartilage, alleviate pain, improve mobility and reduce arthrosis symptoms in the knee.

As part of the joint project, a clinical (phase I/IIa) study is to be carried out to verify the safety of the treatment. BIONCaRT GmbH received approval to conduct the study from the responsible national higher federal authority, the Paul Ehrlich Institute, in May 2025. Fraunhofer IZI’s part of the project will provide the test products for the planned clinical studies.  

Among other aspects, this includes the aseptic production, formulation and filling of the test products based on a cryopreserved cellular intermediate product which is to be produced by a contract manufacturing organisation. Furthermore, this part of the project also includes the execution of all release-relevant quality inspections of the final product, as well as packaging and preparation for shipping to the clinical test centres.

In a previous project, the scientific and technological preconditions for the pharmaceutical production of the clinical test products were established and an update of the product list was obtained under the current manufacturing permit of Fraunhofer IZI in accordance with section 13 of the German Medicines Law. In addition, the product has already undergone numerous tests at GLP conditions in the Fraunhofer IZI GLP test facility. These involved checking for undesirable biodistribution and tumorigenicity.

Project partners
BIONCaRT GmbH (formerly BioPlanta GmbH); Dresden Technical University | University Centre of Orthopaedics, Trauma and Plastic Surgery; Dresden Coordination Centre for Clinical Studies

The Department GMP Cell and Gene Therapy of Fraunhofer is collaborating with Iovance Biotherapeutics Inc. (San Carlos, CA, USA) on the technology transfer and subsequent continuous manufacturing of allogeneic feeder cells used in Iovances’ Tumor Infiltrating Lymphocyte manufacturing process. This collaboration supports Iovance’s upcoming European clinical trials for the treatment of solid tumors in metastatic melanoma and cervical carcinoma.

Iovance Biotherapeutics, Inc. is a clinical-stage biotechnology company focused on the development of cancer immunotherapy products for the treatment of various cancers. The Company's lead product candidate is an adoptive cell therapy using tumor-infiltrating lymphocyte (TIL) technology being investigated for the treatment of patients with metastatic melanoma, recurrent and/or metastatic squamous cell carcinoma of the head and neck and recurrent and metastatic or persistent cervical cancer. For more information, please visit www.iovance.com.