Projects

All six participating centers collaborate in the realization of 12 projects in the common diseases cancer, metabolic and cardiovascular diseases, as well as diseases of the nervous system, infectious and lung diseases.

Cancer - Second iMed funding period

PROJECT 1: Multi-Scale Integrative Biology of Head- and Neck Squamous Cell Carcinoma (HNSCC) - Molecular Consequences of the Metabolic State and HPV - Infection Status on Radiotherapy Response.
(Lead DKFZ /NCT)

Investigators:
DKFZ: Amir Abdollahi, Jürgen Debus, Jochen Hess, Wilko Weichert, Christof von Kalle, Manfred Schmidt, Christian Schwager
HMGU: Claus Belka, Horst Zitzelsberger, Stephan Herzig, Kristian Unger, Julia Heß

Project summary: Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. Exogenous carcinogens (e.g. tobacco- and alcohol consumption) and infection with high‐risk types of human papilloma virus (HPV) are considered the major risk factors for HNSCC. During the past decades evolution in precision radiotherapy and multimodal combinations with chemotherapy and targeted agents (anti‐EGFR) have substantially improved the management of HNSCC. However, local recurrence and distant metastasis are still the two major patterns of therapy failure the disease. To further individualize and improve therapy, a link between the molecular landscape of HNSCC and the treatment response/clinical outcome is urgently needed. We aim to employ an integrative HNSCC biology approach via analysis of clinical- and multi­scale omics data to better understand this complex disease towards identification of novel molecular stratifiers and candidate therapeutic targets. A unique strength of our approach over other prominent international initiatives such as the cancer genome atlas (TCGA) is that the high ‐quality standards are applied not only to the multi ‐scale omics data but also to the clinical characteristics, therapy schemes and follow‐up. For example, tumor morphology, stage, HPV status and clinical course is provided for the entire cohort, consisting of locally advanced HNSCC patients homogenously treated with radiochemotherapy in the frame ‐work of comparable national (DKTK, ARO ‐0401) or local (NCT/LMU) radiotherapy protocols. In contrast, in the most recent TCGA report (Nature 2015) on the molecular landscape of HNSCC only 65% of patients studied received radiotherapy with heterogeneous regimens (variety of doses, only 31% with >60Gy, ± chemotherapy). Moreover, only 16% (45 out of 279) were tested at diagnosis at their clinical centers for HPV status by means of p16 staining or in ‐situ hybridization. Finally, HNSCC patients with different localization and diseases stage e.g. locally advanced vs. initial metastatic stage are conglomerated in TCGA and similar initiatives (Stage I+II: 39.4%, Stage III: 14% and Stage IV: 46.6%).  The reference cohort (training set) of our proposed iMed initiative for HNSCC will built on the well ‐ defined clinical setting and comprehensive multi ‐scale data generated in the frame ‐work of DKTK/ARO/HIPO ‐POP, i.e., genome‐wide methylation analysis (450K), chromosomal aberration (copy number variation, CNV), transcriptome, including non ‐coding microRNA (miR) and DNA ‐mutation (deep ‐ and targeted ultra ‐deep next generation sequencing, NGS) data. A central task of our iMed proposal will be to integrate these data towards discovery of regulatory hierarchies and circuitries underpinning the influence of key variables affecting therapy outcome in HNSCC. Moreover, experimental studies are proposed to uncover the functional link between several parameters such as e.g., the impact of the metabolic state on radiosensitivity, and the potential of radiotherapy to unmask tumor/HPV‐related epitopes for an effective eradication of HNSCC by the immune system. In parallel, molecular ‐ and clinical data are generated for the iMed validation cohort consisting of HNSCC patients treated in Heidelberg and Munich. This novel iMed cohort will provide a solid foundation for rigorous validation of generated hypothesis and discovered candidate biomarkers. The major objective of this project is to identify the molecular mechanisms governing radiosensitivity as the function of HPV‐infection status, the influence of patients’ immune response (T ‐Cell repertoire) and metabolic status on different clinical outcomes, i.e., local tumor control, recurrence pattern (local, in radiation field, distant) and overall survival. Together, this project connects the four key foci of the iMed initiative, i.e., the individualized and stratified cancer therapy with infection (HPV), immune response (TCR) and metabolic state in a unique manner.

PROJECT 13: A preclinical platform based on blood-circulating cancer stem cells to enable individualized targeting of metastatic breast cancer.
(Lead DKFZ/NCT)

Investigators:
DKFZ: Andreas Trumpp, Andreas Schneeweiss
HMGU: Christina Scheel, Stefanie Hauck, Jerzy Adamski, Fabian Theis

The predominant type of cancer in women is Breast Cancer (BrCa). Metastasis formation is the main reason of breast cancer-related lethality and poor clinical outcome is directly related to the development of metastatic disease. Distant metastasis formation is caused by dissemination of tumor cells with clonal capacity (metastasis-initiating cells (MICs) into the blood circulation followed by extravasation and clonal outgrowth in a distant organ such as lung, liver, bone or brain. Blood circulating CTCs are isolatable cells at the interface between localized and metastatic disease. The number of CTCs is prognostic for metastasis formation and overall survival in many tumor entities. Work from the Trumpp/Schneeweiss groups (DKFZ/NCT) and others has demonstrated that CTCs are a heterogeneous population with respect to their capacity to re-initiate metastasis. Next to differences in-between patients cancers (inter-tumor heterogeneity; tumor subtypes) there is a significant intra-tumor heterogeneity within the same patient. This is mainly caused by two biological phenomena: genetic and epigenetic (cancer stem cell) heterogeneity. Tumor heterogeneity is seen as one of the major hurdles with respect to the future improvement of clinical outcomes for breast cancer patients. CTCs are an accessible source of patient material to monitor disease progress before during and after therapy. Moreover, CTCs may be used to dissect intra-tumoral heterogeneity at the molecular level and used to develop diagnostic-prognostic-predictive tools. However, this would require to expand primary patient-derived CTCs for molecular and functional assays, including drug screening. Despite some success in short-term culture of metastatic cells from pleural effusions, certain CTC-populations, and establishment of xenografts in NSG mice, this has not been accomplished yet in a robust and efficient manner. For this purpose, the Trump/Schneeweiss groups have joined forces with the Scheel group, which has achieved a technological breakthrough by efficient long-term expansion of single primary human mammary epithelial cells in 3D-culture, recapitulating normal mammary gland development as well as invasion and self-renewal of BrCa cells.

The joint goal is to generate the first 3D preclinical platform of primary cells derived from breast cancer patients to perform a series of genomic, cellular and pre-clinical drug assays on the same patient sample. This will represent a powerful tool to monitor and analyze tumor development while patients are under treatment and which will be used to discover predictive biomarkers as well as treatment strategies.

Cancer - First iMed Funding Period

Individualized therapy in colorectal cancer
(Lead: DKFZ/NCT)

Investigators:
DKFZ: Philipp Beckhove, Stefan Fröhling, Hanno Glimm, Magnus von Knebel‐Doeberitz
HZI/TWINCORE: Frank Pessler, Dietmar Pieper, Irene Wagner‐Döbler
MDC: Matthias Selbach

Project summary: Colorectal cancer (CRC) is the most frequent cause of cancer-related death in the Western world. Increasing knowledge of the heterogeneity of disease-driving genetic lesions and tumor-initiating cellular components as well as the prognostic and therapeutic impact of anti-tumor immune response in CRC holds the promise to transform CRC patient care. This projects aims to develop molecular and immunologic diagnostics and individualized treatment strategies against tumor progression and metastasis formation in CRC. Individualized diagnostics will focus on the interplay of molecular and functional heterogeneity within individual microsatellite-stable and unstable tumors, their role in tumor progression and metastasis formation. The project will measure the response of the individual immune system against tumor-initiating cells to address the question which immune response can ultimately protect from tumor progression and tumor relapse. Individualized therapeutic development will focus on molecular and immunotherapeutic targeting of tumor-initiating cells on the basis of molecularly and functionally defined and validated target molecules and/or pathways involved in tumor progression, metastasis and immune surveillance. Functional characterization will assess proteins affected by progression-relevant mutations by quantitative proteomics and microbiomic and microbial metatranscriptomic analyses. Systematic development of the specific aims will pave the way towards diagnostics and treatment strategies tailored to the specific needs of individual patients with CRC.

Determination of quantitative systemic molecular readouts of genotoxic signaling networks for individualized cancer therapy.
(Lead: MDC)

Investigators:
DKFZ: Roland Eils, Peter Lichter, Christof von Kalle, Thorsten Zenz
MDC: Gunnar Dittmar, Alexander Löwer, Claus Scheidereit, Clemens Schmitt, Matthias Selbach, Jana Wolf

Project summary: A prevailing problem in current cancer therapy is the poor individual predictability of long-term responsiveness to genotoxic treatment. This is in part due to a lack of predictive biomarkers and systemic molecular data describing the individually distinct networks of oncogenic lesions and genotoxic stress-responsive gene products that are present in subgroups of malignancies. The ultimate aim of the project is the identification of transcriptomic, proteomic and metabolomic signatures, scrutinized by quantitative network models, to classify the activation state of genotoxic stress-induced signaling pathways in tumor cells, with a primary focus on lymphoma. Central genotoxic stress response factors (including NF-κB and p53) are activated by irradiation or chemotherapy and undergo complex interdependent regulations, which may be modulated in a context dependent manner to determine if treated tumor cells undergo programmed cell death, evade into senescence or remain resistant to treatment. Modelling of lymphoma-relevant oncogenic lesions in the mouse and the ultimate comparison of therapy-induced readouts between mouse and humans (crossspecies investigations) will be used to identify individual predictors of therapeutic efficiency. This may allow predicting the susceptibility to already available or emerging drugs which target key modules in the response pathways.

Secondary prevention and outcomes of colorectal cancer.
(Lead: DKFZ/NCT)

Investigators:
DKFZ: Hermann Brenner, Jenny Chang-Claude, Michael Pawlita
HMGU: Jerzy Adamski, Hans-Werner Mewes, Annette Peters
HZI: Dietmar Pieper, Irene Wagner‐Döbler

Project summary: Perspectives of secondary and tertiary prevention are promising for colorectal cancer (CRC), a common, relatively slowly growing cancer. However, currently established markers for early detection, risk and prognostic stratification provide insufficient discrimination for personalized medicine. In this project, the contributions of novel molecular markers, including genetic and epigenetic, proteomic, metabolomic, microbiomic and serolomic markers will be evaluated to enhance discrimination of CRC risk and prognosis. The synergistic, joint use of the best available infrastructure and -omics platforms in the initiative and the uniquely large cohorts of screening participants and CRC patients established by the applicants will enable timely and precise estimation of the contributions of novel molecular markers, over established markers in CRC early detection, risk and prognostic stratification. The goal of the proposed project is the development of personalized prevention and screening strategies.

 

Metabolic and cardiovascular diseases - Second iMed Funding Period

PROJECT 4: Novel Polypharmacological Approaches for the Treatment of Obesity and Diabetes
(Lead: HMGU)

Investigators:
HMGU: Matthias Tschöp, Timo Müller, Christoffer Clemmensen, Stephan Herzig
MDC: Mathias Treier, Thomas Willnow
HZI: Ulrich Kalinke, Frank Pessler

Project summary: The overall aim of this project is the development of novel individualized polypharmacotherapies that optimize an individual’s response to diabetes and obesity intervention. A hallmark is thereby the generation and evaluation of a series of novel therapeutics that combine the beneficial metabolic effects of specific gut and/or steroid hormones in a single molecule of sustained action and improved pharmacokinetics. Coordinated development of these novel pharmacotherapies will be integrated with large-scale metabolic, proteomic, and transcriptomic approaches that will be used to identify gender- and subpopulation-specific biomarkers that take an individual’s genetic and metabolic predisposition into account to optimally predict the efficacy and susceptibility of an individual to a specific polypharmacy. Additionally, advanced genetic and proteomic platforms will be utilized to predict which peptides and nuclear hormones can be combined together to potentially deliver synergistic efficacy, particularly by analyzing how the peptide hormone influences the interactome and cistrome of the nuclear hormone receptor. Thus, it is necessary that we expand our current toolbox of medicines that we can select from in order to maximize the potential of a more personalized approach to diabetes intervention.

PROJECT 5: Combining minor genetic susceptibility genes and environment for personalized prevention of type 1 diabetes
(Lead: HMGU)

Investigators:
HMGU: Anette-G. Ziegler, Ezio Bonifacio, Fabian Theis, Christiane Winkler
DKFZ: Christof von Kalle
UFZ: Irena Lehmann

Project summary: The development of type 1 diabetes is preceded by a preclinical period that includes seroconversion to islet autoimmunity and subsequent progression to diabetes. We have demonstrated that genes and environmental exposure can affect each stage. As part of the work in the first funding period, we identified sets of genetic risk factors which when combined can markedly stratify the risk of type 1 diabetes. We have also recently completed the primary prevention pilot trial Pre-POINT, a dose-finding oral insulin vaccination study in islet autoantibody negative children, and demonstrated immune efficacy with a FOXP3 dominated CD4+ T cell response to insulin in children exposed to the highest insulin dose of 67.5mg.
The aims within the next funding period are to 1) prepare for large scale population based neonatal screening for genetic risk and a randomized controlled phase III trial for primary prevention of type 1 diabetes, 2) develop and improve personalized gene-environment-immune response based staging strategies to predict disease susceptibility and rate of disease progression (for primary and secondary prevention of type 1 diabetes).
Our genetic analyses identified 3 HLA and 9 non-HLA SNPs that together can select newborns from the general population who have an absolute risk of 10% to develop type 1 diabetes (Winkler C, Krumsiek J et al., Diabetologia 2014). We will now develop this into a genetic test to be applied on dried blood spots in newborn testing for type 1 diabetes and have started to establish a program with the Dresden and Munich newborn screening laboratories to test feasibility and integration into the regular newborn screening setting.
We have also performed novel immune response assays and measurements that can stratify the risk of infants developing islet autoimmunity, and have generated omics data in children prospectively followed from birth within our IDF cohort studies including transcriptomics and epigenetics prior to the initiation of islet autoimmunity, and proteomics, metabolomics, and cytokine concentrations after seroconversion. We will complement these data by further analyses of proteomics prior to islet autoimmunity and transcriptomics and TCR sequencing after onset of autoimmunity. This detailed collection of personalized data together with our environmental exposure measures (intrauterine hyperglycemia, infections, vaccinations, air pollution, mode of delivery) in the first years of life will allow us to 1. Develop personalized response profiles that we will integrate into our primary prevention analyses, and 2. Identify what gene-environment combinations and pathways affect immune response, seroconversion or subsequent progression to diabetes.
The program will provide unprecedented early stratification of type 1 diabetes risk, identify relevant pathways to target with therapy, and lead to the implementation of genetic newborn screening for type 1 diabetes and the first randomized controlled phase III trial to test efficacy of preventing initiation of islet autoimmunity in children.

PROJECT 6: Non-invasive imaging of cellular potassium content of the heart and liver using ultra-high-field magnetic resonance imaging.
(Lead: DKFZ/NCT)

Investigators:
DKFZ: Armin M. Nagel, Mark E. Ladd, Reiner Umathum, Heinz-Peter Schlemmer
MDC: Thoralf Niendorf, Beate Endemann, Jeanette Schulz-Menger

Project summary: Magnetic resonance (MR) is a mainstay of clinical diagnosis, but so far clinical MR approaches are limited to anatomic and functional imaging using proton MRI. To close this gap the aim of this project is to develop non-invasive physiometabolic magnetic resonance imaging technology at 7 Tesla that enables for the first time quantitative in vivo assessment of the cellular potassium content (K+). This approach opens an entire new research field of MRI-driven in vivo phenotyping as a link to personalized medicine.
Potassium ions (K+) play a vital role in tumor biology and myocardial function. In healthy cells, the enzyme Na+/K+-ATPase contributes to a concentration gradient across the cell membrane, resulting in a low extracellular K+ (2.5–3.5 mmol/L) and a high intracellular K+ concentration (140 mmol/L). While extracellular K+ concentrations can easily be estimated from laboratory analysis of blood samples, a method for measuring the cellular K+ content in vivo is highly needed and would permit novel insights into pathophysiological processes of major diseases afflicting our society.
Potassium MRI is quite challenging since the sensitivity is about six orders of magnitude less than that of proton MRI used in today’s clinical practice. Additionally, K+ exhibits ultra-short relaxation times, thus requiring sophisticated hardware and dedicated acquisition techniques for fast signal detection.
Recognizing the challenges and opportunities, the project takes advantage of the multidisciplinary synergies and expertise formed around the MR physics groups at MDC and DKFZ. It also leverages the availability of unique MR imaging equipment at both centers that includes whole-body ultra-high-field (7 Tesla) imagers. To build upon the interdisciplinary infrastructure, the MDC will focus on the development of K+ MRI detector technology that enables high sensitivity acquisition of the fast decaying K+ MRI signal. This technology will be supplemented by a transmit/receive detector array dedicated to high resolution 1H imaging for anatomic guidance of image reconstruction algorithms tailored to the needs of K+ MRI. The latter are the stronghold and research interface of the DKFZ, which will develop a novel iterative image reconstruction technique that exploits temporal information along with a priori anatomic information. To enable quantitative assessment of K+ content, the sensitivity profiles of the new MR detectors will be incorporated into the image reconstruction algorithm.   
The synergy that will derive from the new technology will likely eliminate the main barriers to the in vivo study of potassium – a critical dimension of (patho)physiology that is of intense clinical interest. For swift translation into clinical application, the MDC will take advantage of the novel methodology to detail the role of potassium in cardiovascular diseases in human studies while the DKFZ will drive explorations into the pathophysiology and personalized therapy guidance of hepatic cancer and metastasis, with the ultimate goal to advance the diagnosis and therapy of these major diseases. These efforts will include clinical partners at the MDC and DKFZ.

PROJECT 14: Edgotyping of mutationdependent interactions: towards a stratification and personalized diagnosis of patients with neurodegenerative diseases.
(Lead MDC)

Investigators:
DZNE: Peter Heutink, Daniela Berg, Shushant Jain, Matthis Synofzik
MDC: Erich Wanker

Project summary: Genotype‐to-phenotype relationships are far more complicated than the ‘one-gene/one- protein/one-function’ paradigm that was introduced several decades ago (Beadle and Tatum, 1941, PMID: 16588492). Different variants of a gene may cause different diseases (allelic heterogeneity), while the same disease can be caused by mutations in different genes (genetic heterogeneity) (Weatherall, 2001, PMID: 11283697). Recent studies indicate that two thirds of disease‐causing alleles perturb protein-protein interactions (PPIs) (Sahni et al., 2015, PMID: 25910212), suggesting that the investigation of mutation-dependent interactions (“edgotyping”) is crucial to uncover genotype-to-phenotype relationships. In this collaborative project, we aim to systematically study the effects of already known missense mutations in neurodegenerative disease ‐causing proteins (NDCPs) on PPIs and disease- relevant cellular processes. We will focus our efforts in particular on the protein TDP-43 (TAR DNA binding protein 43), which is mutated in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Furthermore, we will examine the effects of mutations in the GBA gene, which represents the most common genetic risk factor for Parkinson’s disease (PD). This gene encodes the lysosomal protein glucocerebrosidase (GCase), which plays a key role in the pathogenesis of PD. For both TDP-43 and GCase previous studies have provided experimental evidence that missense mutations influence their association with partner proteins. How mutations in these proteins affect biological systems or interactome properties, however, is poorly understood. In this collaborative project, we first aim to systematically identify and validate mutation- dependent TDP‐43 and GCase interactions using dual luminescence‐based co-immunoprecipitation (DULIP) and FRET assays, which allow the quantification of PPIs in mammalian cells. Next, we will utilize the generated PPI information to perform systematic gene knockdown screens in disease- relevant cellular models using high‐throughput-high-content (HT-HC) imaging technologies. These studies will provide information on whether perturbations of interactions affect potential pathogenic processes such as abnormal protein misfolding in mammalian cells. Finally, we will assess whether perturbed PPIs can be detected quantitatively in disease-relevant tissues of patients with neurodegenerative diseases. We propose that our “edgetic profiling” strategy combined with HT-HC cellular screening will reveal novel targets and pathways that are altered in the patient-specific context. This type of information may provide much‐needed guidance in efforts to stratify patient populations and to develop better diagnostic tools for neurodegenerative diseases.

Metabolic and cardiovascular diseases - First Funding Period

Quantitative interaction proteomics of disease proteins.
(Lead: MDC)

Investigators:
DKFZ: Michael Boutros
DZNE: Peter Heutink, Thomas Gasser
HZI/TWINCORE: Melanie Brinkmann, Frank Pessler
MDC: Matthias Selbach, Erich Wanker

Project summary: Genetic linkage analysis has successfully identified many genes related to inherited disease, and the recent advance of genome-wide association studies has dramatically accelerated this process. Compared to the pace of discovery of associations of genes to diseases, the functional characterization of these genes and of the mechanisms by which disease causing mutations lead to disease is lagging behind. Many disease causing mutations are thought to alter protein-protein interactions (PPIs). Therefore, studying how disease associated mutations perturb PPIs might yield direct insights into disease mechanisms, and reveal molecular targets for novel individualized therapy. We will use quantitative interaction proteomics to identify interaction partners of proteins related to disease and investigate how interactions are affected by disease causing mutations. The project will therefore help to bridge the gap between genomic data and clinical phenotypes and suggest targets for individualized therapy.

Diseases of the nervous system - Second iMed Funding Period

A comprehensive evaluation of diagnostic and prognostic biomarkers in diabetes progression and neurodegeneration
(Lead: DZNE)

Investigators:
DZNE: Daniela Berg, Thomas Gasser
HMGU: Hans-Ulrich Häring, Norbert Stefan
HZI/TWINCORE: Frank Pessler, Dietmar Pieper
MDC: Erich Wanker 

Project summary: The etiology of type 2 diabetes and of neurodegenerative diseases, such as Parkinson’s disease (PD) and Alzheimers disease (AD) is complex, and it is assumed that these diseases are caused by a multitude of genetic and environmental risk factors, which act in concert on the background of an ageing organism. Increasing evidence suggests at least some of the relevant pathogenetic pathways are shared between metabolic disturbances, in particular diabetes, and neurodegenerative diseases such as PD and AD, or example, insulin signaling and inflammation, amongst others, are important pathways involved in both groups of diseases. Also, type 2 diabetes is a major and well established risk factor for cardiovascular diseases and stroke, and, directly or indirectly, also for cognitive decline, dementia and possibly neurodegeneration in the elderly. In cohorts of patients with diabetes and Parkinson’s disease followed longitudinally at the IDM and the DZNE in Tübingen, respectively, common genomic, transcriptomic, proteomic, microbiomic and imaging diagnostic and progression biomarkers will be identified and related to the clinical findings and course. These markers will then be validated as early diagnostic and prognostic markers in a cohort of still healthy individuals at increased risk for neurodegeneration (TREND-study; see Figure 5.3.1). Identified pathways will also be validated and screened for their potential therapeutic value in suitable high content / high throughput cellular assays developed at the “cellomics” platform of the DZNE. Infection susceptibility, also with respect to immune aging and the influence of incident infectious diseases on progression of neurodegeneration and diabetes will be assessed in cooperation with the HZI.

Infections, inflammation and immune status as risk factors and biomarkers for neurodegeneration and declining neurocognitive function.
(Lead: DZNE) 

Investigators:
DKFZ: Michael Pawlita
DZNE: Monique Breteler, Michael Heneka
HZI: Frank Pessler, Dietmar Pieper 

Project summary: In this project we will combine expertise from epidemiologic, clinical and fundamental research to investigate the interplay between infectious disorders, inflammation and immunity in the development and progression of neurodegenerative diseases at the population level. We will profile participants of the population based Rhineland Study with respect to microbiomic, serologic, genomic and inflammation markers, and investigate how these markers and marker profiles relate to symptoms and early markers of brain degeneration as assessed through detailed cognitive testing and state-of-the art brain structural and functional MRI- imaging.

 

Infectious diseases - Second iMed Funding Period

PROJECT 3: Molecular basis and early predictors of non-responsiveness to hepatitis B vaccination.
(Lead: HZI/TWINCORE)

Investigators:
HZI: Carlos A. Guzman, Ulrich Kalinke, Esteban Vargas, Frank Pessler, Christine Falk
HMGU: Ulrike Protzer, Tanja Bauer, Hedwig Roggendorf, Percy Knolle
DKFZ: Christof von Kalle, Manfred Schmidt
DZNE: Stefan Bonn

Project Summary: Vaccination represents the most cost-efficient strategy to prevent life threatening diseases caused by infectious pathogens, and its therapeutic use for both communicable and non-communicable diseases is also gaining considerable interest. However, vaccine efficacy can strongly vary amongst vaccinees. Several host factors (e.g. age, immune status, genetic background) and vaccine characteristics itself such as antigen structure, adjuvantation, and mode of delivery can influence the response to a vaccine. Thus, long-lasting protective immunity is not always achieved, which in most – if not all – cases depends on the induction of protective antibodies. Therefore, an in-depth understanding of the underlying immunological and molecular mechanisms in vaccine responders and non-responders is essential for early prediction of responsiveness to vaccines in terms of efficacy and safety, to improve vaccination coverage and to advance the development of individualized vaccination strategies.

In the iMed program, the HZI together with Twincore and the Medical School in Hanover, and the HMGU together with the two university hospitals in Munich have already initiated research studies aimed at elucidating the mechanisms of responders and non-responders to an adjuvanted subunit influenza vaccine in the elderly and to a live attenuated yellow fever vaccine, respectively.
Those already ongoing vaccination studies will be complemented in a new project by investigating the variability of hepatitis B vaccine responses. WHO in 2015 recommended the world-wide implementation of hepatitis B vaccines in infants after birth and non-vaccinated children and adults to reduce the disease burden. However, approximately 10% of hepatitis B vaccinated individuals do not adequately respond. So far, the mechanism leading to non-responsiveness and the underlying functional deficits remain elusive. Therefore, the major strategic goals of this project are:

(i) to investigate the underlying immunological and molecular mechanisms, and genetic determinants of responsiveness to hepatitis B vaccination in responders and non-responders,
(ii) to study the responsiveness of hepatitis B vaccine responders and non-responders to an unrelated influenza vaccine,
(iii) to identify early predictive biomarkers for vaccine efficacy, and
(iv) to evolve new strategies to overcome non-responsiveness to hepatitis B vaccination.

The latter will be done in an approved clinical trial, using a third generation hepatitis B vaccine (SciBVac®) that will be tested for its capacity to overcome hepatitis vaccine non-responsiveness.
The multi-scale data obtained from these cohorts will be analyzed by the iMed multicenter systems medicine platforms and by thorough immune monitoring to identify early predictors of responsiveness to vaccines. Mathematical models and training algorithms will be instrumental to determine molecular signatures for prediction of vaccination efficacy. This highly interdisciplinary project encompassing immunology, molecular biology and computer-based approaches expects to give new insights into the mechanisms of vaccine non-responsiveness, to expand the identification of immunological and molecular signatures in responders and non-responders, as well as to determine biomarkers for successful vaccination - until now a main unsolved challenge in vaccinology. It will in addition drive forward the development of highly effective personalized vaccination strategies.

PROJECT 9: Infections and colonizations as personal risk factors of metabolic dysfunction.
(Lead: HMGU)

Investigators:
DKFZ: Michael Pawlita, Tim Waterboer
HMGU: Jakob Linseisen, Annette Peters
HZI/TWINCORE: Frank Pessler

Project summary: Evidence is emerging that infections and colonizations play a role in the development of metabolic diseases. In the current project, using serolomics and targeted microbial detection we will focus on establishing links of past or current infections and colonizations with metabolic dysfunction (metabolomics) and the subsequent patient-related endpoints. In such a way, we will study personalized individual risks of infectious agents for patient-relevant outcomes. We will use and further develop laboratory methods for high-throughput serolomics and targeted microbial detection based on multiplex approaches. We will also develop untargeted and targeted metabolomics methods for in-depth metabolic phenotyping in large epidemiologic studies. Using these methods, we will establish links between past or chronic infections (serolomics in blood samples obtained in the last 15 years) and metabolic dysfunction in the data of
two large cohorts (EPIC and KORA). We will also apply targeted microbial detection methods to samples collected in KORA Follow-up 4 as well as during the pretest phase of the National Cohort and study the links between colonizations/infections and metabolic status in a cross-sectional comparison. By employing existing cohorts (EPIC, KORA), methods will be developed and new knowledge created in order to prepare a large epidemiological research platform for future studies, especially the National Cohort. The future prospect is on applying these methods to a comprehensive study of chronic infections and colonizations on the development of metabolic diseases. (Duration: 2014 – 2018).

PROJECT 10: Identification of individual anti-viral immune signatures and early predictors for successful vaccination strategies
(Lead: HZI and HMGU)

Investigators:
DKFZ: Manfred Schmidt, Christof von Kalle
HMGU/LMU: Stefan Endres, Peter Lichter, Simon Rothenfußer, Ulrike Protzer
HZI/TWINCORE: Carlos Alberto Guzman, Ulrich Kalinke, Frank Pessler

Project summary: Our understanding of antiviral immune responses is still fragmentary and based to a great extent on experimental studies with inbred mouse lines. We have very limited understanding of the underlying mechanisms for differential individual responses to the same viral agents, vaccines and antiviral therapies in humans. The proposed project aims to provide new insights into these clinically highly relevant unsolved problems by initiating prospective observational cohort studies to dissect immune responses to two anti-viral vaccines: the live-attenuated yellow fever vaccine representing a viral infection and a true “priming” (the vaccinees have never been exposed to the antigens), and the seasonal inactivated influenza vaccine as an example of “boosting” (the vaccinees have been exposed to the antigens and/or related antigens before). The second system will also specifically address the aspect of age-dependence in responses to vaccination in terms of both safety and efficacy, which represents a main unsolved challenge in vaccinology.
The long-term goal of the intended cohorts is to generate large data sets containing detailed information about (i) the innate and adaptive immune responses of different individuals to the same acute viral infection/vaccination, including identification of vaccine-specific T cell receptors at the single nucleotide level, and (ii) their genetic and epigenetic make-up, including SNPs and other variances in genes governing the immune response, and (iii) biomarkers associated with a positive outcome of vaccination. These datasets will enable us to correlate genetic variances at specific loci with the measured immune parameters and will help us to understand inter-individual differences in anti-vaccine responses.
The detailed longitudinal characterization of immune responses in vaccinees covering both innate immunity (including NK cell responses) and adaptive immunity will allow answering questions concerning the predictive value of early parameters/signatures on vaccination success, reactogenicity, and safety. Furthermore, the influenza immunization cohort will focus on comparative analyses in individuals 65 years of age, providing new insights into individual determinants of vaccination success or failure among the elderly.
The outcome of this project is expected to help us to design subject-tailored vaccination strategies to stimulate optimal immune responses, limit the cost associated with vaccination of non-responders and reduce the clinical development costs of candidate vaccines by selecting those individuals for efficacy trials who will maximally benefit from the intervention.

PROJECT 11: Molecular diagnostic platform for rapid patho- and resistotyping.
(Lead: HZI)

Investigators:
HMGU: Philippe Schmitt-Kopplin
HZI/TWINCORE: Susanne Häußler, Thomas Pietschmann

Project summary: Infectious diseases continue to be a threat to human health mainly due to newly emerging infections, problematic nosocomial and viral infections, and the continuous development of antimicrobial resistance. The lack of new therapy options underscores the need for optimization of current diagnostics, therapies and prevention of the spread of pathogens. The overall objective of this proposal is to apply a multidisciplinary approach that combines clinical research, clinical microbiology, state-of-the-art research on molecular pathogenicity and resistance mechanisms, next-generation sequencing and MassArray highthroughput genotyping technology to uncover the genetic signatures that determine pathogenicity and antimicrobial resistance profiles of clinically relevant pathogens. We will furthermore apply research towards the development of innovative molecular diagnostic platforms for rapid pathogen profiling in order to accomplish individualized therapy, antibiotic stewardship activities for judicious antibiotic use and the implementation of effective infection control measures, to reduce morbidity and mortality of the patients and to significantly reduce health care costs.

Lung diseases - Second iMed Funding Period

PROJECT 12: Personalized Medicine in Allergy and Lung Diseases.
(Lead HMGU)

Investigators:
DKFZ: Roland Eils, Manfred Schmidt, Christof von Kalle
HMGU: Carsten Schmidt-Weber
HZI: Jochen Hühn
UFZ: Irina Lehmann

Project summary: Overall: The numbers of allergic sufferers have become so prevalent in Germany and throughout Europe (The use of biomarkers in early onset of disease as well as in stratification of allergic diseases will help to prevent severe disease progression and will allow personalized treatment of allergic diseases sub-entities and comorbidities. The high prevalence of this disease warrants early and non-invasive diagnostic tools applicable also in early life.
To develop early biomarkers for disease stratification and personalized, precision interventions the current consortium (Heidelberg, Munich, Braunschweig and Leipzig) focused in the first funding period on 5 biomarker sets using non-invasive RNA, DNA and protein approaches. Biomarkerset 1 & 4 (miRNA/DNA methylation) are taking advantage of cord blood which allows non-invasive early in life diagnosis at birth and current results of the analysis of selected patients will now be extended into larger patient cohorts. Biomarkerset 2 & 3 focus on the TCR/clonotypes (allergen-memory of the immune system) and the work-intensive T cell clone analysis is still ongoing. Biomarkerset 5 is analyzing auto-IgE (protein) and successfully concluded the measurement of 3000 sample of age 10 and requires addition measurements at later age.
In addition, an innovative, non-invasive biomarkerset was included: IL-24 along with Eotaxin-3 and known allergy-relevant analytes will be measured in nasal secretions and sputum samples using the highly sensitive Mesoscale platform. This addition links the biomarker assessment to the DZL asthma cohorts from both children and adults (KIRA & ERA).
In the next funding period, the consortium aims to verify and translate the promising results into clinical practice, by measuring identified biomarkers in already existing cohorts and patient registries (Validation sets 1-5).

Lung Diseases - First iMed Funding Period

Biomarker discovery for early assessment of asthma risk.
(Lead: HMGU)

Investigators:
DKFZ: Roland Eils, Manfred Schmidt, Christof von Kalle
HMGU: Susanne Krauss-Etschmann, Carsten Schmidt-Weber
HZI: Jochen Hühn
UFZ: Irina Lehmann

Project summary: Allergic disease represents systemic diseases with manifestations in multiple organs. It is therefore not surprising that multiple co-morbidities are associated with allergy in a yet largely unknown prevalence. Because the loss of allergen and also of autoantigen tolerance is part of the early disease pathogenesis, it is important to diagnose early immune deviations in allergy exceeding the sensibilization pattern. Some of the seasonal allergic individuals will have a mild disease progression if not spontaneous remission, while other will suffer life-long and some will even progress into severe disease. The use of biomarkers in early onset of disease as well as in stratification of allergic diseases will help to prevent severe disease progression and personalized treatment of allergic diseases sub-entities. The high prevalence of this disease warrants early and non-invasive diagnostic tools applicable also in early life. Within this program the Helmholtz centers in Heidelberg, Munich, Braunschweig and Leipzig propose to build a network project to innovate biomarkers for efficient phenotyping and subsequent personalized treatment in allergy and asthma that will also support the DZL studies. Furthermore the techniques will be made available for already running and planned clinical trials in allergy and asthma at the Munich Allergy Research Center (MARC). The study participants focus on four biomarkers that require only small amounts of blood: Classical and “upgraded” serological markers, DNA methylation, miRNA fingerprints & expressed rearranged T cell receptors (TCR). The latter three biomarkers bear the potential of identifying imprinted phenotypes (e.g. Th2 or Treg imprinted immune responses) even without use of cellular assays. The added value of the proposed project is to increase effectiveness of current asthma therapies by improving early diagnosis and taking advantage of already existing/ongoing cohorts. Using cord blood samples from ongoing birth cohorts (LINA, LISAplus, GINIplus; n>5000), we will identify miRNA-, TCR RNA and DNA-methylation pattern that predict asthma development. In addition to whole genome approaches, we will use these cohort studies to validate miRNA, TCR RNA- and DNA-methylation signatures already discovered in murine models and human T cells. In addition, the level of genome/methylome will be further supplemented by metabolomics and proteomic levels. We recently described metabotypes in our cohort studies and intend to expand asthma subphenotyping with serologic (auto-IgE) and proteomic means. The intention is to link the clinical and the omic-data into a clinical data management system (i2b2 open source; MACOM) to efficiently translate data contents from clinics to bench and backwards. The resulting modeling of the results & experiences will ultimately lead to highly personalized diagnosis and treatment.

 

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