Local targeted immunotherapy for treatment of squamous cell carcinomas

Grantee: Merete Hædersdal, Bispebjerg Hospital

Amount: DKK 2,358,825

Grant category: Research Grants in open competition

Year: 2018

Geography: Denmark

Squamous cell carcinoma (SCC) together with basal cell carcinoma comprises the absolute majority of non-melanoma skin cancers, affecting 150,000 persons in Denmark, equivalent to 3% of the population.

SCC’s cost is consequently substantial, reflected by notable patient morbidity, heavy socioeconomic burdens and significant mortality in immunosuppressed populations.

In oncology, systemic immunotherapies with PD1 and CTLA4 antibodies have had revolutionizing impact on clinical cancer treatment. Recognizing the immense potential of these strategies also for SCC, our vision is to pioneer a new local treatment approach by harnessing the immune system to combat SCC, while at the same time avoiding side effects associated with systemic treatment.

In a three-tiered translational project, we thus aim to deliver PD1 and CTLA4 antibodies through the skin using ablative fractional laser (AFL), effectively opening the door to implementation of topical SCC immunotherapy. The project is executed in collaboration with the Wellman Center at Harvard Medical School and Center for Cancer Immune Therapy at Herlev Hospital. The 3-year research plan comprises preclinical studies on biodistribution and pharmacokinetics in healthy skin, a proof-of-concept study in a well-established murine model for human SCC, and an explorative clinical study in SCC patients from the skin cancer clinic at Bispebjerg Hospital. For patients, topical immunotherapy may constitute a safe treatment with decreased morbidity and the prospect of potentially reduced risk of future SCC occurrence. This in turn will lower the socioeconomic burden of repeated treatments for a large cancer patient group, including high-risk immunosuppressed patients such as organ transplant recipients.

Investigating the role of human periostin in healthy skin and severe eczema

Grantee: Jan J. Enghild, Aarhus University

Amount: DKK 3,045,231

Grant category: Research Grants in open competition

Year: 2018

Geography: Denmark

Severe eczema, also known as atopic dermatitis (AD) is the most common inflammatory skin disease resulting in itchy, inflamed, and swollen skin that is very susceptible to infection. It is estimated that 15-20% of all children and 2-10% of adults are affected, without effective treatment.

Because of this, significant public health burden and the lack of safe and effective treatments, there is a need for novel targeted therapeutics that can help manage symptoms and improve the quality of life for the patients.

The protein periostin is expressed in the skin and is implicated in AD. Significantly, studies have shown that the elimination of periostin in an AD mouse model reduces or completely removes the symptoms making periostin an apparent therapeutic target. However, the physiological functions of periostin remains unclear and a reduction or elimination of the protein in the skin could have severe side effects.

Therefore, a deeper understanding of the physiological role in healthy and diseased skin must be established. The interdisciplinary research team behind this project propose to address these issues and establish the function of periostin using in vitro and in vivo experimental setups including primary cell cultures, zebrafish, mouse models and human specimens combined with advanced biochemical methods. Novel therapeutics are urgently needed, and this project aim is to establish a strategy for the development of new treatment paradigms for AD, leading towards novel, innovative therapeutic strategies.

Skin Proteomic Atlas – a spatially and cell-type resolved landscape of protein expression in the human skin

Grantee: Matthias Mann and Beatrice Dyring-Andersen, University of Copenhagen

Amount: DKK 100,000

Grant category: Education and Awareness Grants

Year: 2018

Geography: Denmark

The skin is an amazing and complex organ that comprises multiple layers and cell types that are functionally distinct.

The aim of this study is to characterize the molecular composition of the healthy human skin by creating an atlas of all the proteins expressed in healthy skin as a function of their spatial location as well as its major cell types.

This atlas, comprising the identification of a global proteomic composition of human skin, will provide an important resource to the community studying the physiology and cell biology of the skin and serve as a basis for future studies comparing the proteomes of inflammatory and oncologic skin diseases.

Publication of the skin atlas will be accompanied by a freely accessible and well-advertised web page portal where information on proteins of interest and their protein profiles in the layers of the skin will be easily available.

LEO Foundation Skin Immunology Research Center

Grantee: University of Copenhagen

Amount: DKK 250,000,000

Grant category: Standalone grants

Year: 2018

Geography: Denmark

Diseases of the skin affect a quarter of the population, more than a billion people, at any given time. Despite impressive progress, especially in the area of immunology in skin diseases, the pace of innovation is not sufficiently high and new treatments are slow to reach patients.

Here, we propose to create a LEO Foundation Skin Immunology Research Center (Skin Immunology Center) that will become a beacon for skin research in Denmark and worldwide.

The Center will identify key questions relating to disease heterogeneity, new pathological mechanisms, and novel therapies of inflammatory skin diseases. With the ultimate aim of helping people with skin diseases in the best possible way, we will launch a focused effort employing cutting edge technologies to advance biological insights and translate basic discoveries to ‘proof of principle’ and then to ‘first in man’ applications (‘bench-to-bedside’). Importantly, observations and questions arising in the clinic will be taken back to the laboratory (‘bedside-tobench’). This team science concept and ecosystem with seamless translation and back-translation between basic biology and the clinic will animate the spirit of the Center from day one.

The Skin Immunology Center will be headquartered at the 12th floor of the Mærsk Tower, the new flagship building at the Faculty of Health and Medical Sciences, University of Copenhagen.

We will bring together the immunology of the skin, its diseases and comorbidities, ‘omics’ technologies, experimental models, and strong clinical integration to develop new stratification paradigms and therapies towards precision medicine. People will form the basis of the success of the Center and we will both empower existing scientists and strategically hire new talent. We will build a pipeline of future top researchers through excellent educational activities. In this way, the Center will incubate and form a new generation of multidisciplinary skin immunology researchers, ready to reshape the field for decades to come.

From the start, we will collaborate across specialties, institutions and geographies. The Skin Immunology Center will aim to have a total of 60 members in the core member research groups when fully operational, a critical mass allowing it to contribute significantly to raising the level and quality of research and education in inflammatory skin diseases.

The existing LEO Foundation Center for Cutaneous Drug Delivery will become an associated and collaborating partner. The Skin Immunology Center will integrate and advance basic and clinical science approaches to skin disease and develop future leaders in the field, while increasing knowledge and awareness of skin and skin diseases among medical professionals, patients and the public.

Bloom Festival 2019

Grantee: Svante Lindeburg, Golden Days

Amount: DKK 500,000

Grant category: Education and Awareness Grants

Year: 2018

Geography: Denmark

Bloom – at the core:

Bloom is an innovative festival about science and nature, which enlighten us on the Universe, the World and Ourselves. Framed in the lush Søndermarken at Frederiksberg in the heart of the capital city of Denmark, where some of the World’s greatest scientists, poets and philosophers have found inspiration through history, Bloom emerges each Spring as a sensual, experimental and thought-provoking festival version of natural sciences.

Prepared and communicated by some of the brightest scientists, thinkers, and artists of our time from here and abroad. By uniting the best from the world of festivals with the best from the scientific world, Bloom arm wrestles with Life’s greatest questions and over two days invite the audience to debates, talks, laboratories, conversations and nature walks under open skies.

GLP-1R signaling in T cells in relation to psoriasis

Grantee: Carsten Geisler, Professor and Head of Department, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen

Amount: DKK 2,000,000

Grant category: Research Grants in open competition

Year: 2017

Geography: Denmark

Recent studies of patients with psoriasis and type 2-diabetes have shown intriguing results: administration of glucagon-like peptide 1 (GLP-1) analogues was found to improve the severity of psoriasis. In another study, while not finding a significant beneficial effect of a GLP-1 analogue on disease score as compared to placebo, patients did report a significant decrease in their disease score as compared to baseline.

This has led a Denmark-based group to team up for further investigation of the effect of GLP-1 analogues on psoriasis, based on, among others, an assumption of a direct effect of GLP-1 analogues on the immune system – with the intention of clarifying if there may be a route to new treatment options for psoriatic patients.

More specifically, the team will investigate if the potential immunoregulatory effect of GLP-1R signalling on T cells in psoriatic plaques could be responsible for the patient-experienced alleviation of psoriasis. The team furthermore hypothesizes that vitamin D may play an important role in GLP-1R signaling and is important for alleviation of psoriasis as Vitamin D upregulates GLP-1R on T cells and low serum levels of vitamin D have been reported in psoriatic patients.

The majority of the experiments will be performed by Anna Kathrine Obelitz Rode under supervision of Martin Kongsbak-Wismann and Carsten Geisler, Department of Immunology and Microbiology, University of Copenhagen. Lone Skov, Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen will be co-supervisor on the project. The project will be performed in close collaboration with Charlotte Menné Bonefeld, Department of Immunology and Microbiology, University of Copenhagen.

The clinical studies in humans will be performed at the Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen in collaboration with Lone Skov.

The pro-autophagic tumor suppressor AMBRA1 as a novel therapeutic target for melanoma

Grantee: Professor Francesco Cecconi, Head of the Cell Stress and Survival Unit (CSS), Danish Cancer Society Research Center (DCRC), Copenhagen

Amount: DKK 3,820,000

Grant category: Research Grants in open competition

Year: 2017

Geography: Denmark

The LEO Foundation has supported this project in appreciation of the fact that malignant melanoma has the highest death toll among skin cancer.

If and when melanoma is not diagnosed and treated early, the cancer may develop and spread to other parts of the body, where it becomes harder to treat and potentially fatal. Therefore, work to find new therapeutic targets for this particular aggressive cancer type is of extreme importance.

Professor Cecconi and his team have extensive and comprehensive expertise on the molecular ‘switch’ AMBRA1, believed to play a significant role in the body’s own defense against diseases such as cancer.

As an example, professor Cecconi was the first to identify the AMBRA1 gene and has been unraveling its multiple functions over the last 10 years. In particular, he has already demonstrated AMBRA1 playing a role as tumor suppressor in vivo, and preliminary data indicates the gene’s supposed role as a therapeutic target in cancer. Very intriguingly, most AMBRA1 mutations were found in melanoma patients.

The LEO Foundation finds this project to be innovative and commends its multidisciplinary approach, putting together different fields of research ranging from cell biology, mouse genetics, biophysics, computational biology and CRISPR/Cas9 technology.

Prof. Cecconi is member of the European Consortium Mel-Plex (Horizon 2020 Marie Curie Action), which includes several international researchers with the common aim of tackling melanoma – and these existing collaborations with melanoma experts will be of great importance in order to accomplish the project.

Instantaneous monitoring of allergic reactions in the skin

Grantee: Stephan Sylvest Keller, Associate Professor, DTU Nanotech

Amount: DKK 600,000

Grant category: Research Grants in open competition

Year: 2017

Geography: Denmark

Allergy is one of the world’s most common chronic conditions. It is caused by immunoreaction of the human body towards in principle otherwise harmless allergens, and the current method for allergy screening and monitoring is the skin prick test (SPT) where different allergens are introduced into the tested person’s skin.

This widely used method, however, is non-quantitative, relatively lengthy and patients might experience unpleasant reactions. Furthermore, clinical evaluation of the SPT requires physical assessment of visible changes of the skin due to local inflammation by an experienced health care professional.

In the supported PhD project, which involves collaboration between DTU Nanotech, the Allergy Clinic at Gentofte Hospital in Denmark, Malmö University in Sweden and the University of British Columbia in Canada, an allergy test based on a micropatch will be developed which may be both more efficient and accurate as well as less cumbersome.

The micropatch will introduce allergens to the skin with carbon micro needles and allow for instantaneous and quantitative monitoring of allergic reactions in the skin through in vivo electrochemical sensing of the histamine released from activated mast cells in the interstitial fluid.

If successful, the new micropatch-based test will provide for less unpleasant allergy tests, in particular relevant with children suffering from atopic dermatitis. Further, a successful micropatch test will be a valuable and effective mean to identify potential immunoreactions towards newly developed topical dermatological drugs.

The project is supported by the LEO Foundation, the Copenhagen Center for Health Technology – CACHET (www.cachet.dk) and DTU Nanotech.

Investigation of atopic dermatitis in Greenland; distinct genotypes, phenotypes, and immunotypes

Grantee: Jacob Pontoppidan Thyssen, Consultant, PhD, DMSc, Assistant Professor, Department of Dermatology and Allergy, Herlev and Gentofte Hospital

Amount: DKK 5,078,619

Grant category: Research Grants in open competition

Year: 2017

Geography: Denmark

The LEO Foundation supports this study aimed at improving diagnostic accuracy and treatment of Atopic dermatitis (AD) in Greenland, and to add to the general knowledge of AD.

The project’s hypothesis is that Inuit children with AD residing in Greenland display a population-specific prevalence, set of risk factors, phenotype, genotype, immunotype, and bacterial load. As part of showing this, it is intended to clarify potential Inuit-specific loss-of-function mutations in filaggrin gene (FLG) addressing the latitude dependent gradient in FLG mutation prevalence and its potential role in providing an evolutionary advantage.

In general, the settings in Greenland differ on many parameters from a conventional western society: The AD study population is expected to be different due to variation in living conditions, diet, climate, and genetic admixture. This is of particular importance to better examine and understand AD etiology and related risk factors and may hopefully provide a break-through in AD research.

In the project, the team will establish a large children cohort in Greenland to estimate prevalence, genotype, phenotype, immunotype, and risk factors for AD. By examining Inuit children with and without AD, compared with Danish children with AD, along with a cohort comparison from collaborating partners, the team will be able to examine whether phenotypic traits correlate with genotype, immunotype, ethnicity, or environmental factors, including gut and skin microbiomes.

The study offers an exclusive opportunity to examine AD in a homogenous small population in a secluded environment, and is foreseen to contribute to increased understanding of AD as an overall term, hereby its phenotype, genotype, immunotype, and specific risk factors. Both to understand better the pathogenesis of AD, and to improve and implement diagnostic tools for Greenlandic patients with AD.

Development of elastin-based biomaterials for wound healing

Grantee: Assistant Professor Andrea Heinz, LEO Foundation Center for Cutaneous Drug Delivery, Department of Pharmacy, University of Copenhagen

Amount: DKK 1,472,000

Grant category: Research Grants in open competition

Year: 2017

Geography: Denmark

Wound healing is a complex biological process involving interaction of different types of cells, mediators, and components of the extracellular matrix.

In particular, re-epithelialization, closure of the wound by the epithelial cells, is a crucial step as it re-establishes skin continuity. The process, however, may be impaired in various pathological conditions such as diabetes, leading to the development of acute or chronic non-healing wounds.

This project, involving participants from Denmark, France, and Germany, aims to develop wound dressings based on novel polymer- and protein-based biomaterials capable of delivery of bioactive molecules. The basis will be elastin, an extracellular matrix protein with unique properties such as elasticity and biocompatibility.

In order to form the 3D scaffolds needed for wound dressings, state-of-the-art electrospinning will be utilized and hydrogels will be prepared by in vitro cross-linking of elastin-based peptides. The conditions of preparation will be tuned to produce a biomaterial of desired mechanical properties, which will then be characterized physio-chemically using a range of analytical techniques.

Addition of bioactive peptides and growth factors will allow for stimulation of wound healing. The materials will be tested in vitro using human fibroblast cell cultures and in vivo using animal wound models.