GMP Cell and Gene Therapy


Manufacturing of clinical investigational medicinal products for the clinical development of new CAR-T cell therapies

Since 2021, the Fraunhofer Institute for Cell Therapy and Immunology (Fraunhofer IZI) has been supporting the international research-based pharmaceutical company Bristol-Myers Squibb in several of its European CAR-T cell development programs.

The collaboration includes process transfer for manufacturing and quality control according to pharmaceutical standards (Good Manufacturing Practice – GMP). After the cellular products and intermediates have been added to the manufacturing authorization of the Fraunhofer IZI in accordance with Section 13 of the German Medicines Act, Fraunhofer IZI manufactures and releases batches required to provide supply of investigational medicinal product for the relevant BMS clinical trials in Europe.

CAR-T cell therapies have been added to the spectrum of cancer treatments in recent years. CAR-T stands for "chimeric antigen receptor T cell". This type of therapy uses the body's own immune system to attack cancer cells.

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

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.

Validation of manufacturing and quality controls for a novel cell therapeutic to be used in the treatment of focal cartilage defects (MSC CartiCure)

The aim of the project is to validate a manufacturing process, including safety-relevant quality controls, for a novel cell therapeutic to be used in the treatment of focal cartilage defects in the knee.

Developed by BioPlanta GmbH, the product is based on mesenchymal stem cells derived from the umbilical cord. This kind of cell boasts an exceptionally high level of immune tolerance, making it suitable for allogeneic therapy concepts. The immunomodulating properties of mesenchymal stem cells have an anti-inflammatory effect, activate regenerative processes, and help restore hyaline cartilage. The project's therapeutic goals are therefore to relieve pain, improve mobility and reduce symptoms of arthrosis in the knee.

The collaboration project will also establish the scientific and technical requirements for the pharmaceutical manufacture of the investigational medicinal product and for dispensing it to patients as part of a clinical trial. The product is to be classified as an advanced therapy medicinal product (ATMP) and falls under the “tissue engineered product” category.

In line with both German and European regulations, validation of the manufacturing process and the respective safety-relevant analytical methods (quality controls) are central to verifying the safe, robust and reproducible manufacture of the ATMP. This includes testing for sterility and bacterial endotoxins. A secondary aim of the project is to update the assortment list covered by Fraunhofer IZI’s existing manufacturing authorization pursuant to Section 13 of the German Medicinal Products Act (AMG).

The product has already undergone extensive testing under GLP conditions in the GLP test facility at Fraunhofer IZI with regard to potential undesirable biodistribution and tumorigenicity. 

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ROR1 CAR-T PoC initiative: CAR-T cells for the treatment of breast and lung cancer

Loading the tubing set for selection onto the CliniMACS Plus
© Fraunhofer IZI
CliniMACS Plus device for T-cell selection.

Cancer is the second most common cause of death in Germany. For years now, the number of new cancer diagnoses has seen a steady rise. There continues to be an enormous need for new therapeutic options to treat all kinds of cancer. In 2017 and 2018 respectively, the US Food and Drug Administration (FDA) and the European Commission approved the first ever form of cell and gene therapy for the treatment of cancer – CAR-T cell therapy. CAR stands for chimeric antigen receptor, which is expressed through a genetic modification on the T cells. The receptor identifies and binds specific antigens on cancer cells, subsequently activating a targeted immune response. 

This revolutionary type of therapy also lies at the heart of the ROR-1 CAR-T research project. ROR-1 is a tyrosine-protein kinase transmembrane receptor, which is strongly expressed during embryonic development, but rarely on healthy adult cells. A high level of ROR-1 expression has been detected on mantle cell lymphoma tumor cells as well as in the case of breast cancer. CAR-T cells designed to target surface molecule ROR-1 are to be used to address hematological tumors such as mantle cell lymphoma but also solid tumors such as breast and lung cancer.

In order to manufacture this kind of therapeutic agent, immune cells are taken from the patient’s body by means of leukapheresis. T helper cells and cytotoxic T cells are then selected by magnetic cell separation. The genetic material for the CAR is introduced into the genome of the T cells via a non-viral gene transfer using the “Sleeping Beauty” transposon system (jumping gene). This reprograms the T cells in such a way that they perceive ROR-1-positive cancer cells as “foreign” and eliminate them by releasing cytotoxic messengers. The reprogrammed cells are multiplied and administered to the patient intravenously.

The project is being funded as a pilot project under the proof-of-concept initiative launched by the Fraunhofer-Gesellschaft, the Helmholtz Association and Deutsche Hochschulmedizin in order to promote the translation of innovative research projects. With the help of this funding, preclinical trials investigating the safety and efficacy of the ROR-1 CAR-T cells have been conducted at Fraunhofer IZI and the pharmaceutical manufacture of the therapeutic agent has been established, with the aim of achieving clinical translation in a phase I / II study (first in man).

Test batches were produced in the project to begin with; these batches were used to optimize the process in line with the stringent production requirements under GMP conditions and to qualify the necessary equipment. After successfully establishing the process and determining the required specifications, three successful validation batches were produced in the clean room and the analytical methods were established. 

Using the cell products generated in these validation batches, the analytical methods relevant to microbiological safety (mycoplasmas, sterility, bacterial endotoxins) and the verification of genomic safety (determining the vector copy number) were also validated. Finally, a product stability test was performed, which culminated in the successful realization of an additional batch. Once the validations were complete, an application was made to and granted by the competent authority to include the investigational medicinal product in the existing manufacturing authorization pursuant to Section 13 of the German Medicinal Products Act (AMG).

Fraunhofer Institute for Cell Therapy and Immunology launches collaboration with Iovance Biotherapeutics,Inc.

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 

Finished projects


Manufacture of Kymriah®

Development of an additive production platform for biodegradable, patient-specific breast implants for natural breast tissue reconstruction
(This project was co-financed by tax revenues on the basis of the budget approved by members of the Saxon state parliament.)

Development of an additive production platform for biodegradable, patient-specific breast implants for natural breast tissue reconstruction

Obtaining of a manufacturing authorization for CardAP-Cells

autoCard study

Manufacturing DCVax®-L for the American biotech company Northwest Biotherapeutics, Inc.

Manufacturing and quality control of EpiDex (autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes for treatment of chronic wounds) together with euroderm GmbH Leipzig / Germany

Manufacturing and quality control of autologous stem cell preparations from cord blood (InnovaCB) together with Innovastem GmbH Leipzig / InnovaStem S.r.l. Brescia / Italy

Process transfer and manufacturing of the Dendritic Cell-based investigational medicinal product Cvac™ for the Australian biotech company Prima BioMed Ltd.