Scientific Collaborations

The German Research Foundation is the main source of public funding for peer-reviewed, high-level science in Germany. The LIT participates in various research groups associated with the Foundation:

SFB/Transregio 305

‘Striking a Moving Target: From Mechanisms of Metastatic Organ Colonization to Novel Systemic Therapies’: addresses mechanisms of metastasis and their therapeutic inhibition. A key aspect of this, the immunological regulation of metastasis, is being investigated by scientists at the LIT.

SFB/Transregio 221

‘Modulation of Graft-versus-host and Graft-versus-leukemia Immune Responses After Allogeneic Stem-Cell Transplantation’ at the integrated graduate school of TRR 221.

SFB 1404 ‘FONDA’

‘Fundamentals of Workflows for the Analysis of Large Scientific Data’: this CRC explores methods to increase productivity in the development, execution, and maintenance of data analysis workflows for large scientific datasets. The LIT is involved in this CRC via the ‘Algorithmic Bioinformatics’ working group.

SPP 2202

‘Spatial Genome Architecture in Development and Disease’: the main goal of this priority program is to investigate the structure-to-function relationship of higher metazoan genomes with high spatial and temporal resolution in study systems relevant to genome integrity and development or disease. The LIT—with its NGS Core Facility—participates in functional and mechanistic studies in vitro and in vivo, using model systems and human samples to deepen understanding of how spatial genome architecture is related to the above processes.

FOR 2858

‘The Importance of the Translocator Protein (18kDa) (TSPO) as a Diagnostic and Therapeutic Target in the Nervous System’: TSPO is a protein with multiple functions, particularly in the nervous system. As part of this research group, LIT scientists are analyzing the significance of TSPO for the regulation of immune responses in the brain—for example, in the progression of brain tumors or autoimmune reactions.

The LIT participates in BMBF-joint programs—in cooperation with pharmaceutical/biotech companies—to develop central processes for the production of cells as a pharmaceutical product and to bring them to clinical application.

GD2-IL18CART

Clinical phase I study of the safety, dose-finding, and feasibility of adoptive T-cell therapy with GD2-IL18 CART in patients with relapsed or refractory GD2-positive solid tumors.

Saturn-3

‘Spatial and Temporal Resolution of Intra-tumoral Heterogeneity in Three Hard to Treat Cancers’: the aim of this consortium is to uncover the complex mechanisms that determine the interaction of cellular, genetic, and epigenetic processes in the development of cancer.

In partnership with academic/clinical consortia from the German Cancer Aid, the LIT is evaluating innovative products and new strategies for adoptive T-cell therapy in academic phase I trials (‘investigator-initiated trials’). These are proprietary CAR-T cell developments with completed preclinical evaluations.

‘Improving CAR-T Cell Function Through CRISPR Activation and Interference’

In this project, the LIT is establishing a versatile and flexible CRISPR interference and activation system (CRISPRi/a), which allows scientists to manipulate gene expression in CAR-T cells in order to improve their function. In contrast to classical CRISPR genome editing, CRISPRi/a is based on gene-expression manipulation without cutting the DNA, thus reducing the risk of genomic mutations and translocations. In addition, CRISPRi/a enables the activation of endogenous genes and the fine-tuning of gene-expression levels, which are used to favorably alter the expression of therapy-relevant transcription factors, cytokines, and stimulatory, as well as inhibitory, surface receptors. Furthermore, the Institute will establish a new concept for the improvement of CAR-T cells based on CRISPRi/a manipulation of distal non-coding gene regulatory DNA elements (‘enhancers’), which should enable signal-dependent gene manipulation.

‘T-Lock’

‘Dissecting T-Cell Resistance of Tumours in Therapy with Immune-Checkpoint-Blocking Antibodies’: In this consortium, LIT scientists use genome-wide screening methods to systematically identify different tumor types’ common resistance mechanisms to immune-checkpoint therapies. These will be used to develop personalized methodology for predicting and breaking through immune resistance in tumors.

CEA-CD30

CD19/CD22

The LIT participates in and coordinates EU-collaborative projects at a European level. It does so within the framework of regular Research Consortia or via the Innovative Training Network (ITN)—for the training of young scientists (PhD fellows). The LIT plays a pivotal role as a training center with a particular expertise in specialized technologies for engineering immune cells and adoptive T-cell therapies that strengthen or surpress specific immune cell response.

CAR T-Rex

‘National Institute’s Translational and Innovational Development: domestication of cell therapies’ (Horizon EIC 2021 Pathfinder Challenge):

CAR T-REX aims to create a new paradigm for the generation of improved CAR T cells: By combining non-viral gene delivery with precise genome editing of autoregulatory T-cell signaling pathways, CAR T-REX offers the prospect of a new strategy to overcome the mechanisms by which solid tumors (and the immunosuppressive TME) ‘turn off’ the anti-tumor immune response. This potentially expands the utility and safety of current CAR-T technologies.

T-FITNESS

‘Fine-Tuning T-cell networks of exhaustion by synthetic sensors’ (EIC-Pathfinder Challenge):

This EU consortium—coordinated by the LIT—addresses the functional improvement of genetically modified T-cell therapeutics in oncology. The efficacy of these therapeutics against solid tumors is still disappointing. A major obstacle to success is ‘T-cell exhaustion’ that occurs in tumor tissue through repetitive stimulation. This EIC-Pathfinder project aims to develop new synthetic circuits of T-cell stimulation, based on microRNA that are capable of reprogramming the gene expression programs that promote T-cell exhaustion. The T-FITNESS approach to enhancing the performance of anti-tumor T cells is a universal platform that can be adapted to current and future cellular immunotherapies—including TIL, CAR-T and TCR-T therapies—to treat all types of malignant tumors.

INCITE – ‘Immune Niches for Cancer Immunotherapy Enhancement’ (FET Open)

The INCITE project aims to improve current approaches to cancer immunotherapy by generating more robust and active memory phenotypes in anti-cancer T cells such as CAR-T or TCR transgenic T cells.

PAVE – Marie Curie EU Training Network

The PAVE consortium focuses on the interdisciplinary development of new nanotechnology approaches for the combined immunotherapy of pancreatic cancer using nanovaccines, cellular immunotherapies, personalized nanomedical approaches, image-guided surgery, and molecular imaging. In this project, scientists at the LIT are investigating tumor-specific T-cell responses and the immune-resistance mechanisms of pancreatic tumors.

NICE

‘Nanomaterials for effective cancer immunotherapy: in vivo engineering of immune cells and tumor microenvironment,’ Novo Nordisk Foundation. The goal of the Center for Nano-Immune Cell-Engineering (NICE) is to transform the logistically difficult, expensive and ineffective chimeric antigen receptor (CAR) T-cell therapy into a ‘standard’ modification strategy for patients. CAR T-cell therapy is a new form of treatment in which cells of the immune system are genetically reprogrammed to seek out and kill tumor cells. In solid tumors, this type of therapy faces a number of hurdles, including a costly manufacturing process, lack of cell persistence and suppression by cells within the tumor. NICE will address these obstacles by using small nanoscale structures that can be developed and deployed to generate CAR T cells in the patient (in vivo), to alter the tumor environment to favor CAR T-cell activity, and to provide continuous stimulation to enhance CAR T-cell persistence for long-term tumor targeting.

LIT researchers are members of several consortia for the European exchange of information and data in the field of immune cell therapy. Examples include:

CA17138
Integrated European Network on Chronic Graft Versus Host Disease (cGvHD)

A FACTT
Action to Focus and Accelerate Cell-Based Tolerance-Inducing Therapies

MAGIC

The LIT plays a central role in the MAGIC consortium at a European level (see above) through its immunomonitoring program.

FANTOM

‘Functional ANnoTation Of The Mammalian Genome’ is a worldwide collaborative project to identify all the functional elements in mammalian genomes. The aim of the sixth edition of the FANTOM project (FANTOM6) is to systematically elucidate the function of long non-coding RNAs (lncRNAs) in the human genome. Within FANTOM, Professor Rehli focuses on understanding the (non-coding) transcriptional landscapes of macrophages and regulatory T cells. This is of fundamental importance in our understanding of how these cells function.

The Vienna Science and Technology Fund (WWTF)

Funded by the WWTF, Professor Edinger is cooperating with Professor Wekerle from the University of Vienna on a clinical study to determine whether the adoptive transfer of in-vitro expanded T-reg cells can induce tolerance after living-donor kidney transplantation.

The Bavarian research network ‘bayresq.net’

The ‘Immune Checkpoints of Commensal Bacteria’ research group comprises scientists from Erlangen and Regensburg, including the LIT, and identifies checkpoints in the immune system as part of the fight against multidrug-resistant bacteria. The immune system works in harmony with the body’s own bacterial environment. These so-called commensal bacteria are also very important for the optimal functioning of the skin. Under certain circumstances, however, some of these bacteria can develop resistance to antibiotics and cause fulminant infections. This research project aims to understand why the immune system recognizes commensal skin bacteria such as Staphylococcus epidermidis, but nevertheless tolerates them and does not induce any active defence mechanisms. This understanding could allow scientists to specifically break through this immune tolerance in order to enable protective immune responses against multidrug-resistant germs. Breaking through these mechanisms could then also be of benefit against tumor diseases.

The Leibniz Association

The LIT has its own tumor and tissue organoid platforms, and has been participating in the Leibniz Research Network ‘Stem Cells and Organoids’ since early 2022. This network aims to optimize the production and genetic manipulation of human organoids, either from primary patient material or from induced adult pluripotent stem cells (hiPS cells), so they can be used in the development of new immune cell therapeutics.