SaxoCell

SaxoCell is a consortium of regional research institutions, clinics and companies that are jointly pursuing the goal of establishing an internationally competitive research and business cluster in Saxony in the field of cell and gene therapies.

The expertise, infrastructure and innovation potential of regional players will be networked and brought together in order to address the following aspects:

• Development of new targets and therapy strategies to expand the range of applications for cell and gene therapies
• Development and bundling of technologies for the validation and optimization of cell and gene therapies
• Development of new manufacturing processes to increase the availability and cost effectiveness of cell and gene therapies
• Establishment and optimization of structures to accelerate technology transfer

Core facilities

• Dresden University of Technology and University Hospital Dresden
• Leipzig University and University of Leipzig Medical Center
• Fraunhofer Institute for Cell Therapy and Immunology
• Klinikum Chemnitz gGmbH

SaxoCell is funded by the Federal Ministry of Education and Research (BMBF) as part of the "Clusters4Future" initiative.

The SaxoCell member institutions work together with other partners in 12 specific research and development projects as well as in overarching innovation-promoting measures (SaxoCell Hub) and technology platforms.

Spokesperson

Prof. Dr. Dr. Ulrike Köhl
Fraunhofer IZI & University of Leipzig Medical Center

Prof. Dr. Frank Buchholz
Technical University of Dresden

Prof. Dr. Martin Bornhäuser
Carl Gustav Carus University Hospital Dresden & National Center for Tumor Diseases (NCT)

The Fraunhofer IZI contributes various competencies and technologies to the SaxoCell cluster:

• Development of T-cell- and NK-cell-based immunotherapies
• Preclinical validation of cell and gene therapies (in vitro and in vivo)
• Development and optimization of manufacturing processes for cell and gene therapies
• Pharmaceutical manufacturing of cell and gene therapies and critical starting materials for clinical trials
• Digitization and automation solutions for the development and production of cell and gene therapies

Projects coordinated / participated in by Fraunhofer IZI (second funding phase)

The Sleeping Beauty transposon system is a powerful tool permitting stable genetic engineering of T cells without involving viral vectors. This aims to ensure improved safety profiles as well as more cost- and time-efficient production processes for T cell-based therapeutics. 

As part of the SB-TRACT project, preconditions for the clinical development of CAR-T and TCR-T cell therapies are being developed. This includes the optimization of the Sleeping Beauty technology and the development of preclinical lead candidates of transposon-modified T cells for the treatment of solid tumors. In addition to the development of suitable production protocols for the (partly) automatic production on commercially available production platforms, technical and regulatory obstacles are to be identified and solution strategies for later development phases are to be developed.

As part of this project, Fraunhofer IZI is contributing its expertise in the field of non-viral gene transfer methods and the development of GMP-compliant production processes for cell and gene therapeutics.

In some instances, T cell-based treatments for hematological cancers involve serious side effects. While the graft-versus-host disease (GvHD) constitutes the main complication in allogenic cell therapies, such as hematopoietic stem cell transplants, the cytokine release syndrome constitutes a dangerous overreaction of the immune system following autologous CAR-T cell treatment.

The SafeTy project examines novel technologies for their suitability for treatment and the prevention of this side effect. 

This includes clinical testing of ATMPs Palintra® for the prevention of GvHD and studies as to whether this can also be transferred to allogenic CAR-T cell therapies. Another aim is to examine whether the technology of low-energy electron irradiation is suitable for GvHD treatment.

Moreover, extracorporeal photopheresis technology is being examined as a potential treatment for preventing cytokine release syndrome following autologous CAR-T cell treatment.

This project aims to further develop pioneering genome editing methods for cell and gene therapies. These permit the removal, insertion, or modification of DNA sequences in cells. The project will examine various technologies which can be used to engineer the genetic material in (immune) cells to render them useful for therapeutic purposes, e.g., in blood and autoimmune disorders and cancers.

As part of this, Fraunhofer IZI is contributing its expertise in the field of clinical gene transfer. The focus is on non-viral systems, such as lipid nanoparticle transfection using the Sleeping Beauty transposon technology, which is to be used to genetically modify macrophages to develop treatments against autoimmune disorders, e.g., systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) in the future.

Natural killer cells (NK cells) constitute a promising resource for the development of cell-based immune therapies, e.g., to treat cancer and autoimmune disorders. Because of their immunological properties, NK cells are also a candidate for allogenic (i.e. non-patient-specific) treatments, which would provide considerable advantages in terms of production, efficiency, and availability, in addition to their therapeutic potential. In spite of the high potential, a variety of challenges have to be overcome until clinical translation. This, e.g., includes genetic engineering methods to increase efficiency and develop suitable production processes ensuring sufficiently high and clinically relevant cell counts. 

The NK Alliance project addresses these aspects and creates the preconditions for the clinical application of NK cell-based therapeutics.

As part of this, Fraunhofer IZI is contributing its expertise in the development of genetically engineered NK cells and GMP-compliant production processes. For example, a GMP-compliant pharmaceutical production process will be established using a CAR-NK cell-based treatment for acute myeloid leukemia and examined for automation options. In addition, various treatment candidates are to be examined for their efficiency and safety in a suitable model system. Likewise, AI technologies will be used to optimize various aspects, such as donor selection, production efficiency, and functionality.

Projects and technology platforms coordinated / participated in by Fraunhofer IZI (first funding phase)

ROR-1 is a tyrosine-protein kinase transmembrane receptor that is strongly expressed during embryonic development but hardly expressed on healthy adult cells. Very strong ROR-1 expression has been detected in tumor cells of mantle cell lymphoma and breast carcinoma. CAR-T cells directed against the surface molecule ROR-1 are intended to target hematological tumors, such as mantle cell lymphoma, as well as solid tumors, such as breast and lung cancer.

As part of the proof-of-concept initiative (Helmholtz, Fraunhofer, university hospitals), preclinical testing of a ROR-1 CAR-T cell therapeutic developed at the University Hospital Würzburg has already been carried out at the Fraunhofer IZI, and a pharmaceutical manufacturing process has been established. The prerequisite for the clinical testing of this immunotherapy was created by obtaining manufacturing authorization in accordance with §13 AMG.

The SaxoCell project UltraCAR-T is already researching the next generation of this therapy and developing as well as validating a shortened manufacturing process. The Fraunhofer IZI is contributing its expertise in the areas of process development and preclinical validation. In close collaboration with the Department of Cellular Immunotherapy, clinical translation is taking place as part of a first-in-human phase I/II study at the University Hospital Würzburg.

Project partner
University Hospital Würzburg, T-CURX GmbH

CAR-T cell-based immunotherapies have already been clinically established as an additional treatment option for certain hematologic cancers. Limitations currently still exist in the restriction to a few indications, as well as in the complex and personalized production and, thus, in the availability of these novel therapies. Comprehensive research activities and strategies are needed to expand both the range of indications and the availability of cellular immunotherapies. One approach is based on natural killer cells (NK cells), which are also suitable for non-personalized (allogeneic) forms of therapy due to their immunological properties. In the CAR-NK 4.0 SaxoCell project, various aspects are being investigated and developed that lay the foundation for establishing CAR-NK cell therapies.

This includes preclinical studies and the preparation of a clinical trial (phase I) to evaluate an allogeneic, CD123-directed CAR-NK cell therapy for the treatment of myelodysplastic syndrome (MDS).

In particular, the Fraunhofer IZI is developing and testing processes that will enable the fully automated and digitally controlled production of CAR-NK cells in the future.

In addition, the project aims to further develop pioneering research approaches that address the effectiveness and range of application of NK cell-based therapies. These include bi-specific CAR-NK cells and combination therapies with multispecific compound molecules (ICE - Innate Cell Engager), with the aim of increasing both specificity and efficacy. In particular, the Fraunhofer IZI is developing technologies for the genetic modification of NK cells and establishing corresponding manufacturing processes. In addition, preclinical studies are being carried out to evaluate efficacy.

Project partner
Klinikum Chemnitz gGmbH, Universitäty Medicine Leipzig, Affimed GmbH, Miltenyi Biotec B.V. & Co. KG

The main complication that occurs after hematopoietic stem cell transplantation is graft-versus-host disease (GvHD), which is often fatal or causes severe long-term damage with the need for permanent therapy. Clinical symptoms are general immunologically triggered inflammations that preferentially affect the skin, intestines and liver. Pathophysiologically, GvHD is triggered by immunocompetent T cells from the donor, which recognize antigens from the patient and then trigger tissue-damaging inflammatory processes.

As part of the SaxoCell project OPTIX, an anti-CD4 antibody Palixizumab® (developed by the Fraunhofer IZI) is to be transferred to clinical application. Ex vivo incubation of the transplant with the antibody induces immune tolerance to the patient's antigens, thereby reducing the risk of GvHD. To achieve this, a GMP-compliant manufacturing process will first be established in order to subsequently realize a clinical trial (phase I/II, first-in-man). This is to be accompanied by further research that will help to establish the specific mechanism of action.

Project partner
Klinikum Chemnitz gGmbH, Tcell Tolerance GmbH, University Medicine Leipzig, University Medicine Dresden

SaxoCell Omics brings together state-of-the-art cellular and molecular measurement methods and associated expertise in data processing and interpretation. In addition to providing efficient and harmonized processes for diagnostics and monitoring, the platform provides cross-project support in the identification of mechanisms of action, new targets and treatment resistance, the establishment of improved quality criteria for manufacturing processes and the development of predictive biomarkers.

The Fraunhofer IZI is, in particular, contributing its expertise in bioinformatics, next-generation sequencing and cell analysis.

Partner
Leipzig University, ecSeq Bioinformatics GmbH, Lipotype GmbH, DKMS Life Science Lab, Miltenyi Biotec B.V. & Co. KG

As part of SaxoCell Systems, a cross-project concept for the automated production of cell therapeutics is being developed. With the long-term goal of establishing an automation platform, new process modules are being developed, AI technologies and machine learning methods are being evaluated and aspects of quality management and GMP compatibility are being integrated. The technology platform should enable the cluster partners to robustly scale up the production of cell therapeutics for clinical scale in the future.

In particular, the Fraunhofer IZI contributes its expertise in the development of GMP-compliant manufacturing protocols and quality controls. In addition, a training concept for ATMP manufacturing processes is being developed and implemented at the institute.

Partner
Dresden University of Technology, Leipzig University