Basel Cell Tissue Gene Therapy Platform

Mission Statement:
to promote research and clinical application of cell , tissue and gene therapy products in Basel

Coordinating committee:
Jakob Passweg (University Hospital Basel), Ivan Martin (Department of Biomedicine), Paul Zajac (ETH Zürich)

 

Forschungspruppen

 

Natural Killer Zellen (NK)

Natürliche Killerzellen können Tumorzellen erkennen und eliminieren. Ein Protokoll zur Expansion und Aktivierung von NK ist erfolgreich etabliert und bei Patienten mit Plasmazellmyelom angewandt worden. Weitere Projekte bei Patienten nach Stammzelltransplantation und bei Patienten mit akuter Leukämie sind in Vorbereitung.

 

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Tumor-infiltrierende Lymphozyten (TIL)

Tumor infiltrierenden Lymphozyten (TILs) als patienteneigenes Therapieverfahren ist für solide Tumorewie zum Beispiel beim schwarzen Hautkrebs (Melanom) etabliert worden. Sie erlauben, vom Patienten T-Zellen gegen den Tumor zu gewinnen, die in einem zweiten Schritt dann vermehrt und letztlich dem Patienten im Sinne einer personalisierten Immuntherapie zurückgegeben werden. Prinzipiell kann eine Aktivierung und Expansion von TILs auf alle Arten von soliden Tumoren angewandt werden. Diese Methode hat vor allem ein grosses Potential, da es die bereits etablierte Immuntherapie in der Onkologie mit den sogenannten «checkpoint inhibitoren» unterstützen und erweitern kann. Daher werden TILs als zukünftige Therapie-Optionen aktuell durch das Kompetenznetzwerk Immuntherapie des Tumorzentrums im Universitätsspital Basel prioritär weiterentwickelt.

 

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Virus-specific T-cell Therapy against Cytomegalovirus, Epstein Barr Virus and Adenovirus

Viral infections remain a leading cause of morbidity and mortality in immunocompromised patients particularly after hematopoietic stem cell transplantation (HSCT). Prophylactic or preventive strategies applying anti-infective drugs are counterbalanced by substantial toxicity, development of resistant variants and delayed immunological reconstitution of the host. Moreover, for some pathogens, standard anti-infective treatment is not available. Adoptive transfer of pathogen-specific T cells is promising in restoring immunity and thereby preventing and treating infections. A protocol to select virus-specific T cells has been established in 2014 to treat patients with cytomegalovirus, Epstein Barr Virus and adenovirus infections after HSCT.

 

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Cell therapy for repair of cartilage injuries in the knee

It is known that cartilage injuries in the knee joint can lead to pain and restriction of movement that in the long-term increases the chance of suffering from degenerative joint diseases such as osteoarthritis at older age.
The orthopedic/traumatology Departments at the University Hospital Basel use a cellular therapy to repair cartilage defects in the knee joint in clinical studies. With a so-called tissue engineering approach, the patient's own cells are used in a special laboratory (GMP clean room) to generate cartilage tissue, which is then implanted in the cartilage defect where it can heal.

Although the method is currently used mainly for non-degenerative cartilage injuries, first applications have already been made in patients with osteoarthritis. Doctors and researchers plan further use this application in a future clinical trial. Thanks to this innovative method, Basel is one of the leading centers in Europe in the field of regenerative healing of cartilage defects.
The laboratories in Basel, as well as the tissue-engineering processes meet all the regulatory requirements of Good Manufacturing Practice (GMP) and, like the study itself, have been controlled and approved by the Swiss Agency for Therapeutic Products Swissmedic and the ethics committee.

 

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GMP facilities

Good Manufacturing Practice (GMP) is a system to ensure that medicinal products intended for human use are consistently produced and controlled according to appropriate quality standards. Swiss manufacturers of medicinal products must comply with international GMP standards set forth by the European Union. These GMP standards are built on three pillars: 1) Pharmaceutical substances and products intended for human use are to be manufactured at sites that are adequately equipped, 2) the producer has to demonstrate appropriate professional and technical knowledge that is provided by qualified staff, and 3) a pharmaceutical Quality Assurance (QA) system needs to be established by the manufacturer. Two GMP laboratory units participate in the Basel Cell Tissue Gene Therapy Platform: The GMP core facility of the Department Biomedicine is located on the 4th floor of the ZLF and the site of the GMP facility of Hematology is in the Labormedizin at the USB Klinikum 2. Both GMP laboratories provide services to individual research groups (“Users") that permit the manufacture of advanced therapy investigational medicinal products (ATMP) to be used in clinical trials.

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Experimental Transplantation Immunology & Nephrology

Our lab is interested in understanding molecular pathways involved in immune regulation. We focus on two main areas:

  1. Development of new genome engineering-based concepts for cellular therapy
  2. Understanding of microRNAs and microRNA-regulated genetic networks in T cells.

Ground-breaking advances in genetic engineering technologies are propelling cell therapies to the frontline of medical research and practice. Major advances in synthetic biology provide new tools to reprogram and enhance cells as therapeutic agents. The combination of cell therapy, genome engineering and synthetic biology provide exciting opportunities to develop the next generation of therapies. We recently developed a new concept termed “allele engineering” and are currently exploring how to implement this principle for radically new cell therapy approaches. In addition, we are investigating how to improve cell therapies, e.g. CAR T cells, based on our work on microRNAs.

Link Research Group

Transplantation Immunology & Nephrology

 

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Brain Tumor Immunotherapy

Glioblastoma multiforme (GBM) is a fatal brain tumor that is resistant to all treatments. Besides other non-neoplastic stromal cells, the tumor microenvironment (TME) of GBM consists of a large, dynamic compartment of immune system related cells. Main players of the immune TME (iTME) are tumor infiltrating brain-resident microglia, macrophages, and T-cells. GBMs are capable of subverting the iTME to facilitate their own growth by re-educating it for their own purposes. Therefore, instead of targeting the tumor cells directly, modulation of the iTME is likely to be a promising approach to combat the disease. Multiple strategies that target either adaptive or innate compartments of the iTME are currently being evaluated.  

Previously, we designed novel orthotopic patient-derived xenograft mouse models with genetically color-coded macrophages and microglia, and modulated tumor-associated macrophages and microglia (termed tumor-associated macrophages, TAMs) of the GBM-iTME by pharmacological means. This in vivo modulation prompted both macrophage- and microglia-induced tumor cell phagocytosis. Moreover, it led to morphological changes in microglia, detectable with cranial in vivo imaging. The efficacy of our therapeutic intervention was preserved in mice lacking Ccr2, limiting macrophage recruitment to the brain. GBM phagocytosis by microglia was sufficient to lessen the tumor burden significantly. Under  treatment, macrophages changed their transcriptional profile towards a pro-inflammatory, M1-polarized signature, whereas microglia displayed a loss of M2 genes. Thus, microglia are a potential target of innate iTME modulation in GBM.
Genetic and pharmacological microglia modulation in syngeneic brain tumor models  
The interplay between the adaptive immune system and microglia in the setting of innate immune modulation has not been studied thus far. Based on the results of our previous research, we hypothesize that microglia reprogramming can elicit an adaptive immune response. To test this, we are going to determine the response of the adaptive immune system in GBM after genetic or local pharmacological microglia modulation in vivo. Furthermore, we will combine local microglia modulation with systemic T-cell checkpoint inhibitors to achieve therapeutic synergy.

Combinatorial tumor and microglia targeting  

Strategies to specifically target GBM neoplastic cells, e.g. with signaling pathway inhibitors, have failed for similar reasons. Therefore, we hypothesize that local reprogramming of microglia within the GBM-iTME facilitates the action of tumor-specific strategies. Among others, EGFRvIII is a promising tumor antigen currently used as a target in clinical trials. Thus, we are going to combine local  microglia modulation with intratumoral EGFRvIII-specific chimeric antigen receptor (CAR) T-cell application to induce better tumor control. 

Glioblastoma region-specific microglia heterogeneity

GBM tumor cells display a vast regional heterogeneity. However, the phenotypical differences of tumor-associated microglia in human GBM are unknown. We hypothesize that intratumoral microglia exhibit a region-specific functional heterogeneity, influenced by paracrine crosstalk with the tumor cells. This is especially important at the invasion zone of the tumor, where tumor recurrence prevails. To assess this microglial heterogeneity, we aim to characterize the region-specific phenotype of tumor-associated microglia in defined locations of resected GBM tissue obtained from a mouse model, and from patients.

Our lab has a direct connection to the Neurosurgery Department of the University Hospital Basel, and we are able to obtain, process and analyze tumor samples based on intraoperative neuronavigation, intraoperative fluorescence microscopy and excellent in house flow-cytometry facilities. We have a vast biorepository of clinically annotated glioma specimens. Mouse modeling of GBM is performed in patient-derived xenograft models and syngeneic mouse models of GBM. We will perform intravital cranial window imaging to visualize the interaction of important players of the immune microenvironment with GBM cells at baseline and under experimental treatments in vivo. We have setup various collaborations within the DBM: Brain Tumor Biology (Prof. Mariani); Cancer Immunology, (Prof. Zippelius, Rochlitz and Läubli); Tumor Hetereogeneity, Metastasis and Resistance (Prof. Mohamed Bentires-Alj); Tissue Engineering (Prof. Ivan Martin, Dr. Manuele Muraro); Embryology and Stem Cell Biology (Prof. Verdon Taylor, Dr. Claudio Giachino); Brain Ischemia and Regeneration (Prof. Guzman); Molecular Immune Regulation (Prof. Jeker); and with external partners to reach our goal to find more effective treatments against GBM. Our work is funded by the Swiss National Science Foundation (Grant PP00P3_176974) and the Department of Surgery.

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