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Success Stories

Vaccine against cervical cancer

© DKFZ/Prof. Dr. H. Zentgraf

It was a breakthrough in women's health: In 2006 the first vaccine became available for protecting women against cervical cancer, the dangerous long-term consequence of infection with certain papillomaviruses. Scientists at the German Cancer Research Center (DKFZ) made a crucial contribution towards developing this first vaccine targeted against cancer. With his pioneering work, Harald zur Hausen, virologist and for many years Scientific Director of the DKFZ, clarified the link between an infection with papillomaviruses (HPV, human papillomaviruses) and the development of cancer. Moreover, experiments conducted by Lutz Gissmann, also from the DKFZ, together with Matthias Dürst at Jena University Hospital, provided important results showing that certain proteins of the viral capsid can be processed into a non-infectious, and therefore extremely safe, vaccine. Research institutions in the USA and Australia have also been working on HPV vaccination. Longstanding disputes about priority claims were finally settled in 2004, when the US Patent Office recognized the crucial contribution of the DKFZ as the co-owner, with the National Institutes of Health, of the HPV vaccine patents. So when the vaccines reached the market in 2006 and 2007, the DKFZ and the participating scientists were finally able to share in the income from sales.

The innovative vaccine against cervical cancer marks a milestone in the prevention of what is the second commonest cancer in the world and the third-ranking cause of death in women. More than 4,500 women a year in Germany still contract cervical cancer and around 1,500 die from the disease. If all girls were to be vaccinated in time, these figures could be drastically reduced. In 2014, the Standing Vaccination Committee at the Robert Koch Institute recommended lowering the age for HPV vaccination to between 9 and 14, so that more girls than ever can be protected from the infection before they become sexually active. Moreover, at this younger age only two vaccinations are required to afford lifelong protection. The vaccine costs are reimbursed by the health insurers.

Two vaccine products have now received market approval in over 50 countries: Gardasil® from Merck & Co and Cervarix® from GlaxoSmithKline (GSK). Together they produce annual sales in the billions. Both vaccines provide almost complete cover against HPV types 16 and 18, which are responsible for around 70 percent of all cases of cervical cancer. Since Gardasil is also targeted against HPV 6 and HPV 11, which cause other genital disorders such as genital warts (condylomata), approximately 90 percent of these cases can be prevented by vaccination. A successor product, Gardasil 9, has now been approved by the US and European regulatory authorities and has now been available on the German market since 2016. In addition to HPV types 6, 11, 16 and 18, Gardasil 9 is also targeted against five other types (31, 33, 45, 52 and 58), which account for around 20 percent of all cases of cervical cancer.


High-precision radiosurgery of tumors

CyberKnife® / iris collimator
© DKFZ/Marco Müller

On 23. 05. 2012, the DKFZ signed a multi-year research and collaboration agreement with Accuray Inc. from Sunnyvale, California, a world-leading company in the fields of radiation oncology and radiotherapy. This agreement continues the important radiotherapy research project that has been under way for nearly a decade, stressed Euan S. Thomson, PhD, President and CEO of Accuray. The results of these project-specific cooperations with Accuray have included the development of the Iris collimator (Iris Variable Aperture Collimator) by Professor Wolfgang Schlegel and the Division of "Medical Physics in Radiotherapy", which he has led since 1993. The Iris collimator is a beam-shaping device developed for Accuray's CyberKnife® Robotic Radiosurgery System, which enables circular radiation fields to be adjusted to differing diameters. When adapted to a robotic linear accelerator such as the Cyberknife®, treatment times can be shortened by a factor of 2-3 compared to conventional apertures, while maintaining consistency of dose distributions (Echner GG, Kilby W, Lee M, Earnst E, Sayeh S, Schlaefer A, Rhein B, Dooley JR, Lang C, Blanck O, Lessard E, Maurer Jr CR, Schlegel W: The design, physical properties and clinical utility of an iris collimator for robotic radiosurgery. 2009. Phys Med Biol, 54, 5359-80). The Iris collimator represented a further development of the multi-leaf collimator developed by Wolfgang Schlegel in the 1990s, which facilitated three-dimensional conformal radiotherapy of brain tumors with precise, individually-tailored dose distribution, thereby sparing the healthy nerve tissue.

"Accuray was a logical choice for us in selecting a research partner given our longstanding collaboration on the CyberKnife®  System and the company's leadership in imaging systems and motion management", said Professor Wolfgang Schlegel on the conclusion of the collaboration agreement with the American company. The joint projects also include, in close cooperation with Heidelberg University Hospital, researching and expanding intensity-modulated radiation therapy (IMRT) and the treatment options for Tomotherapy® - an Accuray technology for reducing the exposure to side effects during the radiotherapy of tumor patients.


Breaking the diffraction barrier

© DKFZ/Abt. Optische Nanoskopie

Because of the wave-like nature of light, the resolution limit for a light microscope of half the wavelength of the light in use was considered to be insurmountable. With the arrival of the STED fluorescence microscope, Stefan Hell, who was awarded the Nobel Prize for this radical discovery, was able to increase the resolution beyond this limit many times over. Light microscopy resolutions down to around 20 nanometers, i.e. the size of individual macromolecules, are now possible as a result. Hell thereby laid the foundations for nanoscopy and nanobiophotonics. The diffraction limit is overcome on the basis of the process of stimulated emission depletion:  a molecule that is "stimulated" to fluoresce can be "depleted" by a second light beam. When Hell superimposed a ring-shaped "depleting" beam of light, in whose area the fluorescence was turned off, over the center of a laser beam adjusted to a wavelength with fluorescence "stimulation", he was able to cause fluorescence to be emitted only from a spot in the central area that was narrower than the spot of the stimulation light. As the depletion light is intensified, this central area is narrowed down to an ever smaller size. In principle, STED microscopy can achieve resolutions down to the size of molecules by scanning point for point and calculating the image with the computer. The STED microscope developed on the basis of Hell's discoveries by the company Abberior has repeatedly provided convincing evidence of its superior resolving power, providing nanometer-accurate glimpses into the processes of living cells and new insights into how drugs work. When combined with 4Pi microscopy, which had also previously been developed by Hell, STED microscopy can also achieve better resolution of the spatial distribution of nanostructures in individual cells.

In the "Optical Nanoscopy" Laboratory at the DKFZ – and in combination with an ultrafast electro-optical scanner developed by the engineer Dr. Jale Schneider at RWTH Aachen University - an STED nanoscope has been developed, under the direction of Stefan Hell and Johann Engelhardt, that enables images to be recorded in intervals of milliseconds. This is several thousand times faster than has previously been possible with laser scanning microscopes. As a result, dynamic processes within the cell that had not been accessible to optical analysis to date can now be examined in detail.


Tetravalent bifunctional antibodies

TandAb® model
© Affimed 2014

Based in the Heidelberg Technology Park, the company Affimed (now Affimed Therapeutics BV) was originally a DKFZ spin-off formed in 2000 by the immunobiologist Professor Melvyn Little. He has worked with his team to develop various innovative recombinant immune molecules that have been patented by the DKFZ, including a completely new class of bifunctional tetravalent immune molecules known as TandAbs®. This involves an antibody format that possesses two binding sites for each antigen and consists exclusively of variable immunoglobulin domains that are connected to each other by linkers. Unlike other bispecific antibody fragments, TandAbs® are large enough to prevent rapid elimination by the kidneys. For each target they also possess the same binding properties and affinities as IgG antibodies. Moreover, since TandAbs® do not possess constant domains, there is no risk of nonspecific cross-linking of Fc regions with immunoeffector cells or molecules capable of triggering a "cytokine storm". Consequently, serious side effects are not expected.

Affimed had in-licensed the TandAb® technology platform from the DKFZ. Two of the antibody-like anticancer substances are in clinical development: AFM13 for treating Hodgkin lymphoma in clinical phase 2 and AFM11 for non-Hodgkin lymphoma in phase 1; other immune molecules are still at the preclinical testing stage. Affimed has entered into collaboration with Merck/MSD to test combination therapies for Hodgkin lymphomas with AFM 13.

Following a successful IPO in September 2014, Affimed Therapeutics BV (AFMD for short) is now listed on NASDAQ, the American technology stock exchange. Analysts report that Affimed has good prospects for further share price rises. For the DKFZ this represents the second successful exit of a spin-off. The DKFZ profits both from the growth in the value of the shares, which can be sold at a later date, and from licenses through product sales. Affimed invests its income from the IPO primarily in the future development of its innovative antibody programs.


Active substance against the most malignant brain tumor

A glioblastoma in the MRT
© DKFZ/Med. Physik in der Radiologie, Foto: Michael Bock

The company's most advanced drug candidate to date, by far, is APG101 (ApoceptTM), a soluble fusion protein that consists of the extracellular domain of CD95 and the Fc fragment of the immunoglobulin G1. It binds to the CD95 ligand that is needed to activate CD95, thereby blocking the signaling chains mediated by the receptor. The efficacy, safety and tolerability of APG101 have already been demonstrated in a controlled, randomized phase 2 study for the second-line treatment of glioblastomas. Those patients whose tumors showed a newly identified epigenetic biomarker associated with the CD95 ligand were particularly likely to profit from the treatment. Apogenix is currently collaborating with the diagnostics company R-Biopharm AG on the development of an accompanying diagnostic test for identifying those glioblastoma patients who would be expected to show the best response to the APG101 treatment in a personalized treatment strategy.

In preclinical tests, Apogenix was able to show that APG101 restores the formation of blood cells (erythropoiesis) in patients suffering from myelodysplastic syndromes (MDS). MDS is an anemic bone marrow disorder associated with the risk of developing into an acute myeloid leukemia, a cancer of the blood. Apogenix then conducted a phase I clinical trial with APG101 in the treatment of transfusion-dependent MDS patients with severely impaired erythropoiesis in order to test the safety, efficacy and tolerability of the drug. The results of the study are expected in the summer of 2016.

APG101 possesses Orphan Drug Status for the treatment of gliomas in the EU and for the treatment of glioblastomas and MDS in the USA. The company CANbridge Life Sciences (Beijing, China) is responsible for the licensing and marketing of APG101 in China, Macao, Hong Kong and Taiwan. Thanks to this partnership, Apogenix can earn revenues that can then be used, in turn, for its own development in the other countries.


Software for improved diagnosis and therapy planning

© Mint Medical GmbH

Researchers in the Division of Medical and Biological Informatics at the DKFZ, headed by Professor Hans-Peter Meinzer, formed Mint Medical GmbH in March 2010. The DKFZ is co-owner of the company, which aims to develop innovative software solutions for use in clinical practice in order to improve the diagnosis, therapeutic strategies and procedures in cancer. There is strong demand for such software solutions, since the high-resolution imaging methods used in modern medical technology provide such a wealth of data from images of the inside of the body that their interpretation becomes almost impossible to manage in everyday radiological practice. To give doctors a detailed insight into the anatomy and functioning of the human body, and thereby allow them to make an accurate diagnosis and provide the ideal treatment, Mint Medical has developed software products for the automated analysis of image data. These products increase the efficiency, quality and reliability of the findings across the whole radiological process – from the diagnosis, via therapy planning and treatment through to the follow-up investigations.

The company has introduced a certified quality management system and applies this to its products, which are both compliant with medical devices legislation and CE-tested. "Mint Liver" was developed as a tool specifically for the computer-aided diagnosis and therapy planning of liver diseases. It can provide a 3D reconstruction of a patient's liver, simulate various surgical procedures and help determine the optimal strategy for the surgical procedure even before the operation and, if necessary, enable the strategy to be quickly adapted to new findings during the operation.

The software development mint LesionTM facilitates the efficient monitoring and follow-up of cancer treatments. As well as providing quantitative and qualitative statements on the development of tumors during the course of treatment, Lesion™ can also be used to produce assessments according to the established standards in radiology simply, quickly and flexibly. Mint Medical products are now used worldwide in routine clinical practice for cancer screening, cancer staging and for assessing the response to cancer treatments. During clinical trials, LesionTM supports the reporting process in accordance with the criteria. It can be individually configured for case-specific, multicenter clinical trials. As a Clinical Trial Management System that has been approved by the FDA, mint LesionTM can support project management, study-compliant read procedures and data management in the implementation of clinical trials for imaging CROs and pharmaceutical companies. For imaging biomarker analysis, mint LesionTM can cover the whole workflow, including all the associated tasks of imaging biomarker research.

The CEO of Mint Medical GmbH, Dr. Matthias Baumhauer describes the company's vision as follows: "Mint Medical products assign a central role to the patient as an individual in our healthcare system. We therefore believe that our solutions will be an important component of any advanced hospital in the medium term."


Oncolytic viruses to treat brain tumors

Computer simulation of a parovirus
© DKFZ / Antonio Marchini

Parvovirus can enter and kill cancer cells, but they do not cause disease in humans. Since 1992, Professor Jean Rommelaere and his team at the DKFZ have been studying the oncolytic properties of these viruses with the aim of developing a viral therapy against dangerous brain tumors that are almost impossible to treat. Measuring just 20 nanometers in diameter, parvoviruses are among the tiniest of all known viruses. They replicate exclusively in dividing cells but do not cause any serious symptoms in humans. Moreover, they do not insert their DNA into the genome of infected cells so that there is no risk of activating growth-promoting genes. Using the parvovirus strain H1, which normally infects rodents but is also infectious for human cells, the researchers investigated the cellular biology of its oncolytic effect. Working with Dr. Karsten Geletneky of Heidelberg University Neurosurgery Hospital, Rommelaere and his team showed that advanced glioblastomas in experimental animals regressed completely after treatment with parvoviruses and that these animals survived significantly longer than untreated fellow animals. "We were therefore able to demonstrate that cancer treatment with parvoviruses can work. At this stage we just had to continue our work, because we saw a great opportunity to also use our viral therapy to help humans affected by glioblastoma, an extremely malignant type of brain tumor," said Jean Rommelaere.

Since the preclinical studies needed to progress the project through to clinical use are very time-consuming, a partner was sought and eventually found in the company Oryx GmbH & Co KG. Oryx is specialized in taking research projects in cancer medicine through the preclinical and early clinical development stages and selling them to the pharmaceutical industry. In January 2008, the Munich-based company signed a cooperation agreement with the DKFZ and Heidelberg University Hospital, which is also involved in the development of viral therapy. Working together with industrial partners, Oryx coordinated the large-scale technical production and subsequent pharmacology and toxicology testing of the therapeutic viruses as well as the approval procedure with the Paul Ehrlich Institute. Clinical phase I/IIa trials began in the Fall of 2011 –the first time that brain tumors were treated with viruses in Europe. On 12 June 2015, Oryx announced the successful completion of the clinical phase I/IIa trial on the treatment of patients with progressive primary and recurrent glioblastoma with H1 parvoviruses, in which the vaccine was found to be safe. The oncolytic parvoviruses will now be tested on other malignant tumors, including pancreatic cancers.


Early detection of cervical cancer

CINtec® p16 histology of a zervix carcinoma
© mtm-laboratories

Scientists from the DKFZ and Heidelberg University Hospital, under the leadership of Professor Magnus von Knebel Doeberitz, a former colleague of Harald zur Hausen, formed mtm laboratories AG (originally: Molecular Tools in Medicine Laboratories), a company that used to develop, produce and distribute biomarker-based diagnostic products for reliably detecting precursors of cervical cancer. The basis for the patent-protected test kits was the company's own antibody clone E6H4TM, which had been developed specifically for immunochemical applications. The antibody is used to detect the overexpression in cervical cells of the cyclin-dependent kinase inhibitor p16INK4a, a biomarker for the oncogenic activity of high-risk human papillomaviruses (HR-HPV), which can then trigger cervical cancer. The detection of this biomarker served as the basis for in-vitro diagnostic products developed by mtm laboratories, including the CINtec® Histology Kit for use on slides with formalin-fixed, paraffin-embedded sections from cervical biopsies, and the CINtec® Cytology Kit for use on smears and cell samples in a liquid medium. mtm laboratories also perfected this cytology test and marketed the resulting product, the CINtec®PLUS Test, which represents a combination of the biomarker p16 and the proliferation marker Ki-67. This test offers a high level of sensitivity and specificity in the detection of high-grade cervical disease. The clinical benefit of these test kits has been demonstrated and validated in many large-scale studies. They proved to be far more precise in diagnosing cervical cancer and its precursor stages than traditional tests, including the classical cancer test with smear specimens that has been used in millions of patients, the Pap test developed by Georgios N. Papanicolaou.

In 2011, the company mtm laboratories was sold, for a total of 190 million euros, to Ventana Inc., a subsidiary of Roche, the global pharmaceutical and diagnostics group. Following the takeover, Ventana developed another product based on this technology platform, the CINtec® p16 Histology Test. As part of a fully automated immunohistochemistry assay, this enables the doctor not only to detect transformed cells, but also to precisely assign them to risk categories, an extremely important factor in the therapeutic decision.


Cell type diagnosis of metastases using antibodies to cytoskeletal proteins

The cytokeratin skeleton of breast cancer cells
© DKFZ / Lutz Langbein

Towards the end of the 1970s, Professor Werner Franke and his co-workers at the DKFZ carried out comprehensive investigations on certain cytoskeletal proteins known as intermediate filaments and established that, although morphologically similar, they occur in various cell type-specific variants that can be differentiated from antibodies. This specificity is also largely preserved in cancer cells derived from the respective cell types. Thus, for example, the cytokeratins (of which numerous specific subtypes exist) are characteristic of epithelial cells and cancers derived from these cells. Since epithelial cells differ in their cytokeratin subtype patterns, the resulting tumors can also be distinguished from each other. By contrast, vimentin, the protein discovered by Franke in 1978, occurs in mesenchymal cells and derived sarcomas, fibromas, lymphomas, etc. The glial cells in the brain, like the astrocytomas derived from them, contain a specific glial filament protein, whereas neuronal cells and corresponding neuroblastomas in turn contain other cytoskeletal proteins known as neurofilaments. As a result, for the first time reliable cell type diagnosis became possible, which was particularly important for cancers with unknown original tumors. In some types of cancer the cytoskeletal proteins can even be detected in the blood. For example, an elevated level of CYFRA21-1 is an important biomarker for lung cancer. Franke and his team also investigated the desmosomes, specific structures that enable adjacent cells to be held together in the surrounding tissue. They identified various contact molecules that also occur in cardiac muscle cells and give the heart its strength. Mutations in the genes of these desmosomal proteins can lead to serious heart disease and life-threatening ventricular fibrillation because the damaged cardiac muscle cells are no longer able to transmit the electrical signals in a coordinated manner.

In order to meet the worldwide demand for antibodies to cell type-specific forms of intermediate filaments for use in diagnosis and biomedical research, in 1983 Franke, together with the DKFZ immunologist Professor Günter Hämmerling and two other colleagues from Heidelberg University, formed the company Progen Biotechnik GmbH, one of the very first biotech companies in Germany. The specific antibodies were further developed by Progen to produce test kits for the diagnosis of cancer and other diseases, for example rheumatoid arthritis. Immunodiagnosis with antibodies to cytoskeletal and desmosomal proteins has now become an integral part of every molecular pathology laboratory. Progen Biotechnik GmbH was wholly taken over in October 2012 by R-Biopharm AG, under whose umbrella PROGEN continued to supply the existing market and break into new markets.


A radionuclide-coupled substance for the diagnosis and treatment of prostate cancer

PSMA-617 mark of a prostate cancer patient
© DKFZ / Matthias Eder

PSMA, the prostate-specific membrane antigen, is expressed up to 1,000 times more on prostate cancer cells than on healthy prostate cells. It is barely found in the rest of the body. As explained by biotechnologist Dr. Matthias Eder of the Division of Radiopharmaceutical Chemistry at the DKFZ, "PSMA is therefore an ideal target for diagnostic purposes as well as for targeted therapies against prostate cancer." His group developed PSMA-617, a small molecule that is capable of specifically attaching to PSMA and that can be labeled with various radionuclides. When chemically bound to gallium-68, a weakly radioactive diagnostic radionuclide, PSMA-617 can be used to visualize even the smallest clusters of prostate cancer cells in PET (positron emission tomography) scans. "In this way, physicians are able to detect small secondary tumors in other organs or very closely monitor the response to therapy. Diagnostic approaches that have been used in clinical practice to date have not come close to this sensitivity," explained Matthias Eder.

Alternatively, PSMA-617 can also be bound to highly radioactive radionuclides such as lutetium-177 or actinium-225. The radiopharmaceutical is selectively taken up by the tumor cells that carry the PSMA and then destroys these cells from the inside. This could be a very promising treatment option, particularly for patients with hormone-resistant prostate cancers, which are very difficult to treat. At Heidelberg University Hospital, the team led by nuclear medicine specialist Professor Uwe Haberkorn has already used lutetium-177-labeled PSMA-617 to treat individual patients with advanced prostate cancer. After treatment with the lutetium-labeled radiopharmaceutical, levels of the prostate cancer marker PSA fell sharply in around 70 percent of the patients. PET/CT images also confirmed that metastases had shrunk or were no longer detectable. "The results were so promising that we plan to go ahead with a clinical trial as soon as possible to examine whether PSMA-617 is superior to other therapy methods," explained Haberkorn. Although other agents that target the protein PSMA and can be coupled with strong or weak radionuclides are already being developed, they have not proved to be ideal. "They are too unstable, accumulate insufficiently in cancer cells and wash out too slowly from healthy organs," explained the chemist Professor Klaus Kopka, Head of the Division of Radiopharmaceutical Chemistry at the DKFZ. "By contrast, PSMA-617 accumulates in large quantities in tumors and metastases and is stored well in cancer cells."

In June 2015, Matthias Eder, radiochemists Martina Benešová, Klaus Kopka, Uwe Haberkorn and their co-workers received the "Image of the Year Award" and the Berson-Yalow Award at the Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) in Baltimore, USA, for their development of PSMA-617.


Antibody microarrays for screening of biomarkers in cancer

© Sciomics GmbH

Professor Jörg Hoheisel, Head of the Division of Functional Genome Analysis at the DKFZ, has played a crucial role for over twenty years in the development of microarray technology and is now one of the world's leading experts in the field of antibody microarrays. It is only in recent years that such protein-based affinity microarrays have been used on a large scale, particularly for proteome analyses, since the technical challenges are considerable compared to those applicable to nucleic acid arrays: Not only do proteins have to be detected in all their diversity and with all their modifications, the structures of the protein molecules and their biophysical and biochemical properties also differ hugely. The concentrations of individual proteins differ by orders of magnitude and are constantly changing, just as the whole proteome of cells is continuously undergoing dynamic changes. Nevertheless, antibody microarrays have been increasingly better adapted to these challenges over the years and optimized in terms of their handling and reliability, so that they have now become an efficient, high-throughput instrument for proteome analyses and their applications - such as the search for clinically relevant biomarkers for cancer.

In 2013, Hoheisel and his colleague Dr. Christoph Schröder, formed the biotech company Sciomics GmbH in Heidelberg, which uses its protein microarrays to offer services for medical research, diagnosis and industry including, in particular, biomarker screening, the verification of biomarker candidates, the analysis and localization of drug targets and their signaling pathways and the characterization of antibodies. Schröder is the CEO of Sciomics GmbH, while Hoheisel still acts as a consultant for the company.

The research team at the DKFZ headed by Hoheisel and Schröder has used microarrays from cancer-relevant antibodies to identify, file for patenting and publish a series of biomarker signatures. These microarrays may be important for the diagnosis, prognosis and prediction of cancer. Predictive biomarkers provide information about the possible effect of the therapeutic intervention, whereas prognostic biomarkers deliver information about the patient's illness and its course independently of the treatment. Among other aspects, they are investigating the altered plasma protein composition in patients with chronic lymphatic leukemia and other B-cell lymphomas, as well as cancer-associated proteins in pancreatic carcinoma, a type of cancer which, to date, has proved difficult to treat and usually diagnosable too late. In another study, the scientists have used an antibody microarray to predict recurrences of bladder cancer, which reappears within five years of surgical removal of the tumor in around 60 percent of patients. In their comparison of patients with and without recurrence, they have identified 255 proteins that are present in the tumor in small or large quantities. Twenty of these proteins produced a pattern which, with 100 percent specificity and 80 percent sensitivity, represents a highly promising candidate as a predictive biomarker signature for relapses of bladder cancer.


Strategic partnership with Bayer Pharma to develop innovative cancer drugs

Tumor sample, imbedded in paraffin
© Bayer HealthCare AG

The alliance between the DKFZ and Bayer HealthCare (BHC) is an outstanding example of a collaboration between a major public research facility and an international company in which the partners combine their strengths to pursue common goals that they would find difficult to achieve on their own, explained the former Scientific Director of the DKFZ, Professor Wiestler, who initiated the strategic partnership in 2009. The focus of the collaboration, which has been extended to 2018, is on joint research projects financed in equal parts by the two parties. The projects are aimed at finding molecules, mechanisms and model systems that can provide starting points for the development of innovative anticancer treatments. The partners are also working to develop novel methods of diagnosis to monitor the individual course of disease and therapeutic progress, and help predict the treatment success. The sharing of scientific and technical expertise is ensured through joint decision-making and steering committees for the research projects, regular meetings of the project groups, mutual visits by delegations of scientists and joint symposia. For the DKFZ researchers, depending on the respective work packages the projects also involve research secondments at BHC in Berlin or Wuppertal. In order to translate the results of basic research into medical applications more quickly, the translational research will be further expanded by obtaining input from the National Center for Tumor Diseases in Heidelberg as a modern oncology center with a multidisciplinary approach.

In 2013, the alliance was expanded to include the field of immuno-oncology, and the corresponding researchers at BHC and the DKFZ are working together on more advanced projects in a Joint Immunotherapeutics Lab in Heidelberg. Up to 2.5 million euros a year is being invested in these projects. In total, the two partners will be investing up to six million euros a year in the collaborative oncology research projects for the period 2014 to 2018. If any projects prove successful, the DKFZ will receive a share of the revenues. Of the more than 30 projects initiated to date, many have already reached important milestones and progressed to the next phase of drug development, namely compound screening to identify new potential drug candidates.


Competency cluster in imaging and radiotherapy: the alliance with Siemens Healthcare

7 Tesla magnetic resonance tomograph
© DKFZ / Tobias Schwerdt

In 2006, the DKFZ entered into a strategic alliance with Siemens Healthcare that further strengthens their longstanding cooperation over several decades. The new form of this collaboration involves numerous interdisciplinary teams consisting of doctors, physicists, chemists and computer scientists in the DKFZ "Imaging and Radiooncology" research program, who are working with the "Division Imaging & IT" at Siemens Healthcare on the further development of various imaging diagnostic methods to bring them into line with the requirements of radiotherapists and improve the quality of the medical management of cancer. Also included in the alliance are the University Hospital and National Center for Tumor Diseases in Heidelberg. In this alliance the latest methods will be explored and integrated in new therapeutic strategies. For example, the diagnosis of prostate cancer can be improved by combining magnetic resonance imaging (MRI) with ultrasound, while the combination of MRI with positron emission tomography (PET) can provide quantifiable information on the metabolic activity of the tumor and its malignancy. More precise, faster and better imaging in cancer diagnosis is achieved with the 7 Tesla high field scanner supplied by Siemens and housed in a dedicated steel building specially constructed by the DKFZ in order to protect patients from the strong magnetic field. The high magnetic field strength not only produces stronger signals, but can also be used to create innovative image contrasts to provide information about the oxygen consumption and individual metabolic products in the tumor tissue. This allows conclusions to be drawn about the malignancy of the cancer. Brain tumors, for example, can be diagnosed with hitherto unachievable precision. For treatment with protons and heavy ions, the scientists in the alliance are developing mathematical techniques for optimizing and accelerating the radiotherapy. In October 2012, the Heidelberg Ion-Beam Therapy Center, together with the Helmholtz Center for Heavy Ion Research, commissioned a gantry - the world's only such facility - a gigantic radiation unit that can irradiate tumors with millimeter precision from any angle with heavy ions and protons. The scientists in the DKFZ-Siemens Healthcare alliance are also involved in the software developments, treatment plans and clinical trials for testing the effectiveness of the heavy ion and proton irradiation in various tumors.


Detecting and combating cancer stem cells

Tumor stem cells of pancreas cancer
© DKFZ / A. Trumpp

Established in 2008 by the DKFZ and the Dietmar Hopp Foundation, the Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH) is based on the model of a non-profit public-private partnership, a special type of cooperation between academic science and the private sector. HI-STEM aims to promote the use of results obtained in stem cell research for cancer medicine and develop innovative strategies for diagnosis and treatment. The Managing Director is Andreas Trumpp, who also heads the Division of Stem Cells and Cancer at the DKFZ. Together with his team he is researching all aspects of the biology of tumor stem cells: What markers do they feature? How are they activated? What is their stem cell niche micro-environment like? How do they contribute to the formation of metastases, the primary cause of cancer mortality?

The scientists discovered how the loss of a tumor suppressor gene in healthy blood stem cells leads to leukemia-forming tumor stem cells. Unlike most cancer cells, tumor cells reside in protected niches and only rarely divide. As a result, they are often resistant to conventional cancer treatment. Trumpp and his team showed how dormant stem cells can be activated by chemical messengers, making them susceptible to subsequent chemotherapy. They also provided experimental evidence indicating that the tumor cells circulating in the bloodstream of breast cancer patients are accompanied by metastasis-inducing stem cells (MICs) characterized by the combination of three surface molecules: CD44, which helps cells settle in the bone marrow; CD47, which protects cells from attacks by the immune system, and MET, which enhances the cells' invasive capability. Patients with a large number of such triple-positive cells have particularly high numbers of metastases and a very poor prognosis. The characterization of the MICs leads to improved diagnosis. In cooperation with the pharmaceutical industry, substances that selectively attack the MICs, potentially improving the patient's chances of survival, are already being tested.


High-precision analyses for human gene therapy and immunotherapy

© GeneWerk

GeneWerk GmbH was founded in July 2014 by Christof von Kalle, director of the Department of Translational Oncology at the National Center for Tumor Diseases (NCT) and the DKFZ, and his colleagues Manfred Schmidt and Annette Deichmann. Schmidt and Deichmann are the joint owners and managing directors of the start-up company, in which the DKFZ also has a direct involvement. GeneWerk's highly qualified team possesses unique expertise in gene therapy methods, bioinformatic analyses and regulatory requirements, and is able to use a broad repertoire of highly sensitive molecular genetic analytical methods to address the individual needs of new gene therapy and immunotherapy studies on cancer and other serious diseases and investigate efficacy and safety in the patient in clinical trials. By way of example, the company's own technological developments such as "non-restrictive linear amplification-mediated PCR" [(nr)LAM-PCR] enable scientists to precisely analyze the insertion sites of viruses that are integrated as vectors in human cells, and thereby counteract the risk of tumorigenesis induced by the vector systems.

The analysis platforms offered by GeneWerk include the following: investigation of vector safety in gene therapy through integration site analysis with (nr)LAM-PCR and target enrichment sequencing; qPCR for the simultaneous amplification and quantification of DNA or RNA fragments; immune-repertoire analyses involving the sequencing of the hypervariable region of T-cell receptors to determine the clonal and functional status of a T-cell population; (off)-target analyses for genome editing, i.e. the analysis of nonspecific genome sequence modifications outside the target site using designer nucleases (e.g. zinc finger nuclease, TALEN and CRISP/Cas 9); specific bioinformatics and data management programs for next-generation sequencing projects, whole-genome analyses, modeling and computer simulations.

Gene therapy and immunotherapy are considered to be the great beacons of hope for the treatment of hitherto incurable diseases. Major international biopharmaceutical companies are also becoming increasingly involved in these areas. With its wide range of validated analyses in its pipeline, GeneWerk is targeting this growth market. To satisfy the corresponding requirements, and barely two years after its formation, GeneWerk is pressing ahead with company certification and reorganizing the IT infrastructure so that it is able to efficiently analyze the huge amounts of generated data.


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