Research Area 3: Targeted immunomodulatory therapy

Department of Internal Medicine V, Friedrich-Alexander Universität Erlangen-Nürnberg
Heads: Prof. Dr. Andreas Mackensen and Prof. Dr. Dimitrios Mougiakakos
Contact: andreas.mackensen(at)uk-erlangen.de , dimitrios.mougiakakos(at)uk-erlangen.de

1. Optimization and development of T cell-based immunotherapies against cancer.
2. Immunoregulatory cells in malignant diseases and stem cell transplantation
3. Tumor metabolism and its impact on immune responses
4. Development of innovative metabolic targeting in cancer

Project H: Harnessing immune responses in hematological malignancies by redox-remodeling

Brief description: Emerging evidence suggest that tumor-associated oxidative stress weakens the patients’ immune system and thereby contributes to tumor immune escape and attenuates the efficacy of immune based therapies. In this PhD project we aim to (1) evaluate oxidative stress-induced immune alterations in patients with leukemia and to develop strategies for pharmacologically (2) antagonizing this metabolic condition and for (3) enhancing the resilience of immune cells towards it. The ultimate goal is to boost intrinsic anti-tumor immune responses and to increase the efficacy of immune based therapies. The methods utilized in this translational project will comprise a broad variety of cellular, immunological, and metabolic techniques.

Molecular Oncology Group, Department of Radiotherapy and Radiation Oncology, Klinikum der Universität München
Head: Prof. Dr. rer. nat. Kirsten Lauber

Contact: kirsten.lauber(at)med.uni-muenchen.de

1. Molecular mechanisms of cell death and its modulation by targeted agents.
2. Interaction of dying cells with the innate immune system and its utilization for the induction of adaptive anti-tumor immune responses.
3. Cellular and molecular mechanisms, which contribute to the onset of inflammatory side effects in the context of radiotherapy, e.g. irradiation-induced pneumonitis.

Project I: Combination of radiotherapy with Hsp90 inhibition to enhance the extent and the immunogenicity of tumor cell death for the treatment of sarcomas.

Brief description: The induction of immunogenic forms of cell death by specific radiotherapeutic regimes appears to be a promising approach for the stimulation of innate and adaptive anti-tumor immune responses. The aim of this PhD project is to explore, whether Hsp90 inhibition in combination with radiotherapy can enhance the extent as well as the immunogenicity of sarcoma cell death, and whether this can contribute to the stimulation of anti-sarcoma immune responses. To this end, various molecular, cell biological, and immunological methods will be employed, including in vivo experiments.

Molecular Immunology Group, Institute for Clinical Chemistry and Pathobiochemistry, Technical University of Munich
Head: Prof. Dr. Jürgen Ruland
Contact: j.ruland@tum.de

Our research concentrates on the molecular mechanisms of immune cell activation and of the pathogenesis of cancer. By investigating following questions we want to provide targets for the therapeutic manipulation of the immune system:

1. How do normal immune cells recognize pathogens and by which mechanisms does this recognition initiate immune defense activation?
2. How do pathologically deregulated signals in blood cells lead to malignant transformation and thus to the development of leukemia or lymphoma?

• Project J: Mechanisms of MALT1 in antigen receptor signalling
  Brief description: The protease MALT1 forms together with CARD11 and BCL10 a protein complex that is crucial for antigen receptor-mediated NF-κB signaling for lymphocyte activation and differentiation. We have genetically demonstrated that a selective inhibition of Malt1 protease function enhances inflammatory pathway by inhibiting regulatory T cells (Gewies et al., Cell Rep 2014). Nevertheless, the mechanisms of Malt1 function for lymphocyte regulation are still not well known. A wide array of molecular, cellular, immunological and transgenic techniques, including primary cell culture, flow cytometry and western blotting, will be used to elucidate the functional relevance of Malt1 in antigen receptor signaling.
• Project K: Functional role of CARD11/BCL10/MALT1 complexes in lymphoid malignancy
  Brief description: Altered CBM signaling can be found in a number of lymphoid malignancies with hyperactivation of the CBM complex being a hallmark of lymphomagenesis. To mechanistically study the effects of putative interaction partners of CBM complex members on downstream signaling processes and to investigate their role in driving pathogenesis of lymphoid malignancies, different molecular, cellular and transgenic techniques will be used, including flow cytometry, primary patient sample analyses and inhibitor assays.

1. Mechanisms of tumor-induced immune suppression in pancreatic cancer
2. Tumor immunotherapy based on recognition of cytosolic RNA species by RIG-I-like helikases
3. Development of bifunctional, immunostimulatory RNA molecules for immunotherapy of gastrointestinal cancers
4. Evaluation of 3p-RNA therapy-suited combination compounds (Checkpoint inhibitors, immunogenic cell death inducers)
5. Mechanim of 3p-RNA induced cell death and immunological conseqences

Project L: Immunosuppression in gastrointestinal cancers using 3p-RNA-based combination therapies

Brief description: Pancreatic cancer is characterized by a potent immunosuppressive network entertained by tumor and stroma cells in the tumor microenvironment. Type I interferons (IFN) play a critical role in anti-tumor immunity. Synthetic 3p-RNA molecules activating RIG-I, a cytosolic sensor for viral RNA, can be exploited to induce a therapeutic type I IFN response as well as an immunogenic form of tumor cell death leading to the priming of adaptive anti-tumor immunity. In addition, by adding specific RNA sequences into 3p-RNA molecules siRNA-mediated gene silencing of tumor promoting or immunosuppressive molecules can be combined with RIG-I signaling in a single molecule. We demonstrated efficacy of this approach in several tumor entities, including pancreatic cancer und hepatocellular cancer (HCC). RNAseq of 3p-RNA treated tumor cells revealed potential “escape” mechanisms as well as vulnerabilities, which can be exploited for combinatorial approaches. These include immune escape and metabolic pathways. In addition, robot-assisted drug screening will be employed for an unbiased search for combination therapies using a large compound library. Promising candidates will be tested for in vivo efficacy in relevant murine tumor models.