Contact Press / Media
Dr. Ulrich Blache
Project leader at Fraunhofer IZI, ICON project Designer-NK
Fraunhofer Institute for Cell Therapy and Immunology
04103 Leipzig, Germany
Phone +49 341 35536-3220
Building on the initial successes of T cell-based cancer immunotherapies and expanding both their scope and variety of applications, another type of immune cell is receiving increasing attention in biomedical research: natural killer (NK) cells.
Unlike T cells, NK cells also lend themselves to allogeneic forms of therapy as they can be safely transferred between healthy donors and cancer patients. This facilitates standardizable and cost-effective stock production, which allows the products to be retrieved according to demand.
Before allogeneic NK cells can be employed as an efficient medicine, they first have to be genetically modified and equipped with new receptors that are able to recognize cancer cells. The strategic partnership between the researchers at Oslo University Hospital and the Fraunhofer Institute for Cell Therapy and Immunology focuses in part on modified T-cell receptors (TCR), which are able to recognize fragments of intracellular tumor antigens on HLA-I complexes. Compared with CAR (chimeric antigen receptor) T cells, which can only recognize surface antigens, this makes for a much broader spectrum of potential target antigens.
In order to translate pertinent research findings into clinical application as quickly as possible, process solutions for pharmaceutical production are directly considered and factored in at every stage of development. Fraunhofer institutes IZI and IPA (Institute for Manufacturing Engineering and Automation) are also contributing their experience in the fields of GMP process development and the development of automation solutions for the manufacture of cell therapeutics.
REANIMA aims to provide innovative therapies for heart regeneration. It is the first project in Europe to include results from fundamental research with the aim of translating these into medical applications. The knowledge gained from animal models is to be comprehensively analysed to develop new, regenerative therapies to treat congestive heart failure. This project is funded by the EU Horizon 2020 programme. Fraunhofer IZI is a member of the project consortium which brings together twelve European partners.
Centro Nacional de Investigaciones Cardiovasculares (CNIC)
Grant Agreement No
Cell and gene therapies are innovative treatment methods facilitating curative approaches to severe, previously incurable diseases. This includes therapies using genetically modified cells as advanced medicinal products (ATMP). In CAR T cell therapy, the patient’s own T cells are modified with chimeric antigen receptors (CAR). Both the approved CAR T cells and the majority of new CAR T cells currently being developed are based on the stable genetic engineering modification of the patient’s own cells with the help of viral vectors. However, since the CAR T cell therapy is still a very new method, long-term effects have not been fully studied. Furthermore, persistent CAR T cells partly cause severe side effects. The temporary modification of cells using a messenger RNA (mRNA) coding for the CAR protein constitutes an alternative to the stable version.
The competence platform aims to develop transient CAR cell therapeutics to treat immune-mediated diseases. For this purpose, new mRNA technologies and nano-transporter systems will be developed. As a result, an establishment project is to generate CAR T cells against activated fibroblasts. Human 3D cell culture and tissue models of fibrosis as well as a novel imaging platform will be used for functional testing. Another goal is to transfer this technology to natural killer (NK) cells to develop donor-independent CAR cell therapies.
Moreover, the platform will be used to develop mRNA-based CAR cell therapeutics with a higher safety profile. This results in a transient ATMP approach to the treatment of fibrotic diseases. To cover the future demand for CAR cell therapies, the transition from autologous products (using the patient’s own cells) to allogenic (genetically different) products is supported so that one product batch can be used to treat as many patients as possible.
If the establishment project is successful, further ex vivo models of fibrotic tissues are to be used for CAR cell testing in cooperation with Fraunhofer ITEM. Concurrently, the platform is to be expanded with other cell-therapeutic effects (e.g. T cell receptor-modified cells) and other target indications (e.g. arthrosis) in the medium term.
The launch of the first programmed killer cells (chimeric antigen receptor (CAR)-carrying T cells; product name ”Kymriah” from Novartis AG) has significantly expanded the therapeutic options for blood cancer patients. However, the use of CAR-modified T cells, due to their biological properties, remains below expectations, especially in the treatment of solid tumors. This is mainly due to the fact that the therapeutic cells are often not able to penetrate into the tumor mass. In this context, it is known that the tumor environment (the so-called microenvironment) inhibits the activity of programmed killer cells. To actively address these challenges, the suitability of different starting cells for developing new cell and gene therapeutics will be tested. In this project, CAR macrophages will be used to generate and implement a new cellular therapeutic approach against solid tumors that have been difficult to treat so far. For this purpose, macrophages are isolated from human donor material and subsequently equipped with chimeric antigen receptors (CAR) directed against prominent tumor antigens. The ability of the CAR macrophages to target tumor cells is expected to be maximized by inducing and locally releasing type I interferons (type1 IFNe). In addition, macrophages are expected to reprogram the tumorigenic milieu of the solid tumor into an anti-tumorigenic milieu to force tumor growth arrest while sensitizing tumor cells to standard therapies. According to their biological function, macrophages can further: 1. actively phagocytize tumor cells and 2. present tumor-specific antigens, which in turn activate other immune cells to fight the tumor.
The use of CAR macrophages can greatly expand therapeutic options for various types of tumors. Unlike expensive, patient-specific cell therapeutics, macrophages can also be used and applied from foreign donors (as an allogeneic product). In particular, transport routes and times can be reduced and the availability of therapies for affected patients can be increased enormously.
The project is characterized by its translational character, since not only the conceptual and technical feasibility of CAR macrophages in a biological context will be addressed, but also a standardization of CAR macrophage production with the help of appropriate protocols will be secured and described.
With an incidence of 30 to 40 percent, the graft-versus-host disease (GvHD) is one of the main complications after an allogenic haematopoietic cell transplant. Conventional treatment methods aim for an unspecific suppression of the entire immune system, which can significantly increase the risk of infections and relapses. Moreover, the long-term success to be expected might be low and associated with both hepato- and nephrotoxic side effects. As a result, the development of less straining alternative treatments is urgently needed.
The GMP process development / ATMP design department is developing protocols and methods to prepare the production of the advanced therapy medicinal product (ATMP) Palintra® to prevent GvHD under GMP conditions. Pre-incubation of a haematopoietic cell transplant with an anti-human CD4 antibody reduces undesired immune responses against the host tissue after transplantation. However, the graft-versus-tumour (GvL) effect which protects against relapses is maintained.
As part of the pre-clinical development phase, cell-based functional assays are established. These potency assays can measure the function of the immunotolerance-inducing, anti-human CD-4 antibody in vitro for the first time ever. Moreover, next generation sequencing is to be used to detect changes in the transcriptome of T cells and to draw conclusions regarding the molecular effect of the antibody. Additionally, the treatment efficiency of Palintra® in GvHD prevention is examined in vivo and compared with conventional therapies.
In addition to fulfilling official pre-clinical requirements, the experiments listed above can generate new insights into immunological processes in inducing immunotolerance and into GvHD. These models and insights are particularly important not only for haematopoietic cell transplants, e.g., in leukaemia treatment but also for stem cell transplants for other indications (e.g. autoimmune diseases).
The measure is co-financed with tax funds on the basis of the budget approved by the Saxon State Parliament.
Cell and gene therapeutics, so-called advanced therapy medicinal products (ATMPs), have a very high therapeutic potential. In hematology and oncology CAR-T cell therapy has been used in Germany, for example, since 2018. However, complex logistics processes from centralized production sites and inflexible manufacturing and application schemes make the production of these cell therapeutics very time and cost intensive. In the EU project "AIDPATH" (Artificial Intelligence-driven, Decentralized Production for Advanced Therapies in the Hospital), project partners from industry and research are now working on the development of an automated and intelligent facility capable of producing targeted and patient-specific cell therapy directly at the point of treatment, i.e. in the hospital. In addition, the project addresses the integration of the facility into the hospital environment, taking into account logistics processes as well as data management and data security.
Fraunhofer IZI is contributing its expertise to the project, particularly in the automation of manufacturing processes and plant networking. The main site in Leipzig has long been a central manufacturing and development site for a CAR-T cell therapeutic used to treat certain forms of blood cancer.
The "AIDPATH" project, which started in January 2021, is funded for four years under the European Union's Horizon 2020 framework program for research and innovation under grant number 101016909.
AIDPATH project consortium