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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.


Innate Cell Engagers improve the anti-tumor activity of immune cells

TandAb® model
© Affimed 2014

The company Affimed (NASDAQ: AFMD) was founded as a DKFZ spin-off in 2000 by the immunobiologist Professor Melvyn Little. He and his team developed various innovative recombinant immune molecules that were patented by the DKFZ, including a completely new class of bispecific tetravalent immune molecules called TandAbs®. These antibodies were developed further and ultimately Affimed's antibodies were named ICE® (Innate Cell Engagers). Affimed is listed on the NASDAQ, the American Technology Stock Exchange since September 2014. The company was added to the NASDAQ Biotechnology Index in 2015, and in 2019 it was added to the Russel 2000 and Russel 3000 indexes

ICE® activate innate immune cells, such as NK cells or macrophages, by binding to their receptor CD16A and simultaneously to specific antigens on the tumor cell surface. Once these connections are established, the innate immune cells become engaged and induce tumor cell killing via antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

AFM13, the company's first-in-class ICE®, has demonstrated clinical activity in Phase 1 and Phase 2 clinical trials, e.g. when used as monotherapy in CD30-positive lymphomas and Hodgkin lymphomas. In a study with The University of Texas MD Anderson Cancer Center, AFM13 demonstrated an unprecedented efficacy, when used in combination with allogenic NK cells in patients with CD30-positive Hodgkin lymphoma. In combination with the anti-PD-L1 antibody pembrolizumab in patients with Hodgkin lymphoma, Phase 1 clinical trials resulted in higher response rates than the individual treatments alone.

AFM24 targets EGFR on cancer cells. This allows targeting of EGFR-expressing solid tumors. AFM24's mode of action of does not rely on EGFR signal inhibition, and only uses the tumor antigen as a docking site, which differentiates itself from previous EGFR-targeting therapeutics and potentially offers a novel option for patients who have developed resistances to EGFR signal inhibitory treatments. AFM24 is investigated as monotherapy and in combination with a PD-1 inhibitor or adoptive NK cells.

Furthermore, AFM28, a CD123-targeting ICE® for the treatment of patients with AML, has entered its first clinical study in 2023.

In 2018 Affimed introduced the ROCK® (Redirected Optimised Cell Killing) platform, a tool that allows a modular development of novel ICE®. Several molecules are in preclinical development with promising initial results.

Affimed collaborates with global pharmaceutical and biotechnology companies to improve cancer treatments across a broad range of tumor types. Besides a partnership with Genentech, Roivant Sciences, Merck Inc., Roche as well as a number of academic institutions collaborate with Affimed to bring new options to patients in need.


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 was a global leader in developing biomarker-based in vitro diagnostics with a focus on 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, an established 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 optimized this cytology test and marketed the resulting product, the CINtec®PLUS Cytology Test, which represents a dual staining of the biomarker p16 and the proliferation marker Ki-67. The co-expression of these proteins indicates a transforming HPV infection is present and the woman is at elevated risk for having high-grade cervical neoplasia

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, Roche announced the acquisition of mtm laboratories, which became part of Roche's Tissue Diagnostics (Ventana Medical Systems Inc.). Roche bought mtm for an upfront payment of 130 million EUR plus 60 million EUR upon reaching performance-related milestones. Most recently, in 2020, Roche received the FDA approval of the CINtec®PLUS Cytology Test to aid clinicians' efforts in preventing cervical cancer. FDA considered data from the Roche-sponsored IMPACT (IMproving Primary screening And Colposcopy Triage) trial, which enrolled approximately 35,000 women in the U.S. to clinically validate CINtec PLUS Cytology as a triage test in various screening scenarios. Prior to FDA approval, the CINtec PLUS Cytology test had been used as a triage test for HPV-positive results and mildly abnormal Pap cytology results in Europe, Asia, South America, Canada and Australia. Roche's Cervical Cancer Portfolio covers the entire spectrum of screening, triage, and diagnostic solutions for cervical cancer and constitutes a key factor in the success of WHO's worldwide program to eradicate cervical cancer by 2030. 


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. These investigations demonstrated that, although morphologically similar, intermediate filaments occur in various cell type-specific variants which can be differentiated with specific antibodies. The antibody specificity was shown to be largely preserved in cancer cells derived from the respective cell types. Thus, for example, cytokeratins are characteristic of epithelial cells as well as cancers of epithelial origin. Whereas, vimentin, the protein discovered by Franke in 1978, occurs in mesenchymal cells and derived sarcomas, fibromas, lymphomas, etc. The glial cells in the brain, furthermore as well as derived astrocytomas, contain a specific glial filament protein, while neuronal cells and corresponding neuroblastomas contain different cytoskeletal proteins known as neurofilaments. As a result of these studies, reliable cell type diagnosis became possible, which was particularly important for cancers of unknown origin. For some of the cancer types the cytoskeletal proteins can even be detected in the blood. In this regard, elevated levels of CYFRA21-1 has been demonstrated to be an important biomarker for lung cancer. Franke and his team also investigated the desmosomes, which are specific structures that enable adjacent cells to be held together in the surrounding tissue. They identified various contact molecules that occur in cardiac muscle cells providing the strength to the heart. Mutations in the genes encoding the desmosomal proteins can lead to serious heart disease and life-threatening ventricular fibrillation since damaged cardiac muscle cells are no longer able to transmit 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, Franke, together with the DKFZ immunologist Professor Günter Hämmerling and two other colleagues from Heidelberg University, formed the company PROGEN Biotechnik GmbH in 1983, one of the very first biotechnological companies in Germany. Immunodiagnosis with antibodies against cytoskeletal and desmosomal proteins has now become an integral part of every molecular pathology laboratory. In October 2012 PROGEN Biotechnik GmbH became a 100% subsidiary of the R-Biopharm AG, under whose umbrella PROGEN continues to supply the existing market and break into new markets.

In 2019 PROGEN acquired the exclusive rights from DKFZ for our AAV (Adeno-Associated Virus) antibodies and products based on these AAV antibodies. AAVs are small viruses of the parvoviridae family. AAV derived vectors have gained interest in the field of viral based gene therapy due to several advantages. Amongst others, AAV is known to be non-pathogenic. The absence of any symptoms or human disease being associated with AAVs makes AAV derived vectors a perfect vehicle for the delivery of genetic material to human cells. In the last decade, recombinant AAV (rAAV) vectors have been intensively studied and used for in vivo gene transfer, representing a promising therapeutic approach to target inherited, genetic diseases and many others. In this context, a transgene is inserted into the viral genome, thereby replacing the viral genes for replication and packing. After purification, the recombinant virus can be applied to the patient, transducing the target cells and restoring the defective or missing gene of interest. AAV has been demonstrated to enable long-term transgene expression due to its latent state within the cell. The derived vectors rarely integrate into the genome but reside as episomes in the nucleus, lowering the chance of spontaneous gene alteration. Furthermore, AAV naturally infects a wide range of cell and tissue types. However, the tissue tropism of the different AAV serotypes is determined by the different cell surface receptors used for the attachment to the target cell. As of April 2023, rAAV vectors have been used in more than 300 clinical trials worldwide ( The range of diseases treated with rAAV based gene therapeutics includes inherited diseases like cystic fibrosis, haemophilia B and muscular dystrophy, as well as acquired diseases like severe heart failure and Parkinson´s disease. Some of these AAV derived gene therapies have shown promising results so far and three AAV gene therapies against inherited retinal dystrophy, spinal muscular atrophy and Hemophilia B have already been approved by the FDA.

Starting as a pioneer antibody manufacturer, PROGEN has become a globally operating biotech company and a reliable partner for academia, biotech and pharma. The company developed from an antibody manufacturer to a leading supplier and exclusive provider of AAV antibodies and analytical tools for accurate and reliable AAV titer determination supporting the development of safe and efficient gene therapies. The team consists of life science and AAV experts, many of them DKFZ alumni, and is partnered with specialists within the field of gene therapy and the life sciences worldwide. The company follows their mission to provide high quality products that help advancing new therapies and develop existing research processes safely, quickly and affordably for the life science community.



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 Healthineers that further strengthened their longstanding cooperation over several decades. The new form of this collaboration involves numerous interdisciplinary teams consisting of doctors, physicists, biologists and computer scientists in the DKFZ "Imaging and Radiooncology" research program, who are working with the imaging and IT groups at Siemens Healthcare on the further development of various imaging-based diagnostic methods to bring them into line with the requirements of radiologists and 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 are being explored and integrated into new diagnostic and therapeutic strategies.

For example, Dr. Heinz-Peter Schlemmer's team of the Radiology division at DKFZ is focusing on improving prostate cancer diagnostics 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. Such methods can improve the accuracy of biopsy sampling by making sure that the biopsy needle precisely targets the site of interest. Moreover, they have increased the performance of 68Ga-PSMA PET/MRI by improving the software that analyzes the results of the scan. PSMA is a membrane surface antigen in prostate tissue that can be traced by PET imaging, but is prone to generating image artifacts. Dr. Kachelrieß's team in the X-Ray Imaging and Computed Tomography division has introduced an algorithm that can recognize and remove such artifacts, and thereby improve the accuracy of diagnosis based on PET/MRI scans.

More precise structural and functional imaging in cancer diagnosis is achieved with the 7 Tesla high field MRI scanner supplied by Siemens and housed in a dedicated building specially constructed by the DKFZ with steel shielding in order to protect surrounding electronics 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, for example, 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 and characterized with hitherto unachievable precision. In 2019 Mark E. Ladd, Ph.D., Head of the Division of Medical Physics in Radiology at DKFZ, was a finalist for the German Future Prize alongside his cooperation partners, Christina Triantafyllou, Ph.D. from Siemens Healthineers, and Professor Arnd Dörfler, M.D., Head of University Hospital Erlangen's Department of Neuroradiology. They received the nomination for the development of the first ultra-high field 7 Tesla MRI scanner for clinical use. This technology is able to accurately image anatomical structures as small as 0.2 mm, allowing early diagnosis of not only tumor lesions but also neurological diseases like multiple sclerosis (MS), epilepsy and Parkinson's disease.

For treatment with protons and heavy ions, the scientists in the alliance are developing mathematical techniques for optimizing and accelerating radiotherapy. In October 2012, the Heidelberg Ion Beam Therapy Center, together with the Helmholtz Center for Heavy Ion Research in Darmstadt, commissioned a gantry, the world's only such facility, to form 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 Healthineers alliance have since been involved in developing software, generating treatment plans and performing clinical trials for testing the effectiveness of the heavy ion and proton irradiation in various tumors.

The efficiency and safety of heavy ion irradiation therapies rely on the precise identification of the tumor site, but the current clinical standard method, single-energy CT scans, has weaknesses. To improve accuracy of high-energy beams, researchers of the DKFZ – Siemens cooperation together with colleagues from OncoRay (Dresden) have worked on implementing dual energy CT (DECT) into clinical usage. DECT can provide two images based on two x-ray energies simultaneously that enable a more precise, patient-specific targeting of the ion beam. After the initial success of the cooperation, the team developed a clinically certified software that made this application of DECT available for clinicians at other particle therapy centers.

Since 2019, the partners in the alliance also cooperate in a BMBF-funded project to investigate the use of MRI in particle therapy. Within this project, two MR scanners have been implemented at the HIT facility: one for offline imaging of patients just outside the gantry treatment room and one for experimental purposes in the experimental beam-line. The team is also investigating novel software solutions to directly use MRI for particle therapy treatment planning.

In 2022, the newest generation linear accelerator for radiation therapy from Varian (a subsidiary of Siemens Healthineers) and a 3 Tesla MRI system from Siemens were installed in adjacent rooms in a common bunker of the DKFZ. The two machines are connected by a dedicated patient shuttle, enabling unique research studies for MR-guided radiotherapy. The soft-tissue contrast of MRI provides better delineation of tumor tissue and will enable personalized therapy adapted to changing organ positions and metabolic characteristics of the tumor.


Detecting and combating cancers through cancer stem cell research

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

Cancer cells with stemness properties (leukemic or solid cancer stem cells) are responsible for therapy resistance and consequently drive relapse and metastases, which are the main cause of cancer related deaths. Cancer stem cells (CSCs) can stay dormant in their stem cell niche for long periods of time within the tumor which mediates their insensitivity to anti-proliferative treatment schemes such as chemotherapy. Upon re-activation however, these cells can cause rapid relapse even after a seemingly positive response to therapy.

The HI-STEM gGmbH was co-founded by the DKFZ and the Dietmar Hopp Foundation with the goal to create a dedicated public-private research institute that focuses on tumor stem cell research and guides clinical translational of the latest discoveries in this field. This includes the development of diagnostic tools, and research for innovative therapies to target tumor stem cells in leukemias and solid tumors. The institute is located on the fourth floor of the DKFZ main building in Heidelberg and is directed by Professor Dr. Andreas Trumpp, who is also the head of the Division of Stem Cell and Cancer at the DKFZ. HI-STEM closely interacts with other Heidelberg and national based Institutions/networks, such as the DKFZ, the National Centers for Tumor Diseases (NCTs), Heidelberg University Hospital, the German Stem Cell Network, and the BioRN, a life science research and industry cluster in the Rhein-Neckar region. HI-STEM currently consists of seven research groups including junior research groups. Their main research focus can be specified into three main areas: (1) Hematopoietic and Leukemic Stem Cells, (2) solid and metastasis Cancer Stem Cells (Breast-, Colon- and Pancreatic cancer) and (3) regenerative therapies for degenerative diseases using stem cell reprogramming.

Hematopoietic stem cells (HSCs) located in the bone marrow are typically dormant, have long-term self-renewal activity and control live long blood production by generating proliferative progenitors that differentiate into functional mature blood cells. HI-STEM characterized the molecular mechanisms mediating long-term self-renewal and stemness down to the single cell level and showed that the state of dormancy is protecting the genomic integrity of HSCs. This is critical as mutations in single HSCs lead to clonal hematopoiesis caused by mutant HSCs with a clonal growth advantage. Clonal hematopoiesis becomes quite common with higher age and is associated with increased risk of cardio-vascular diseases such as cardiac infarction due to mutated macrophages generated by mutated HSCs. Additional mutations in this clone may then lead to the generation of leukemic stem cells (LSCs) driving Acute Myeloid Leukemia (AML). HI-STEM research has identified novel metabolic vulnerabilities of LSCs that next to metabolic pathways also regulate DNA methylation and also identified a super-enhancer (BENC) that controls the MYC oncogene. In another study a mechanism could be identified that allows LSCs to escape Natural-Killer (NK) cell mediated immune surveillance and the team identified a strategy using PARP1-inhibitors to re-establish NK recognition. These pre-clinical data are soon further evaluated in the NAKIP-AML clinical trial in which AML patients with minimal-residual disease after therapy are treated with PARP1-inhibitor followed by transfusion of haplo-identical NK-cells. These should now recognize and eliminate the residual therapy-resistant LSCs. Most recently, HI-STEM reported a new biomarker to identify patients that would/would-not respond to first-line therapy with Venetoclax (BCL-2 Inhibitor) / Azacytidine (hypomethylation agent). This is an important clinical advance as clinicians have two choices to treat fit AML patients at diagnosis: Combination chemotherapy or Venetoclax / Azacytidine. The biomarker measures the combinatorial expression of BCL-2 family member proteins specifically in LSCs from which a score (MAC-Score) is calculated that predicts response to Venetoclax/Azacytidine with high accuracy and may spare patients a highly toxic chemotherapy.

The main cause of death in patients with solid cancers are metastases. Cancer stem cells (CSCs) play an important role in metastasis and researchers of HI-STEM have identified and characterized blood circulating CSCs in breast cancer patients that have the capacity to initiate new metastasis. They discovered a connection between cellular stress and metastases and identified the Jun-kinase signalling pathway as one of the main stress switches of breast cancer CSCs. In pancreatic cancer HI-STEM identified an aggressive and metastatic subtype that differs in a specific methylation pattern that activates endogenous retroviruses leading to an inflammatory, but targetable tumor microenvironment. Finally, with overexpression of CYP3A5 a novel mechanism mediating therapy resistance to chemotherapy was identified and the insights are currently evaluated in a clinical trial (IntenSify) by treating patients with a CYP3A-inhibitor in combination with the chemotherapeutics paclitaxel. Next to a significant number of patents, researchers of HI-STEM have published >200 papers (since 2008) with last-author publications in highest ranked journals including Nature, Science, Cell, Cancer Discovery, Cell Stem Cell, Nature Cancer or Cancer Cell among others.


ProtaGene Continues the Legacy of GeneWerk's Commitment to Safer Gene and Cell Therapies

© ProtaGene GmbH

GeneWerk acquired equity investment from Ampersand Capital Partners in 2020 to expedite its growth and establish a U.S. market presence. Then, in July 2021 GeneWerk, BioAnalytix, and Protagen Protein Services (PPS) merged to form ProtaGene.

PPS and BioAnalytix were leading global contract research organizations primarily specializing in advanced analytical services for protein-based biopharmaceutical products. The combination of the three organizations established a world-class CRO designed to meet the evolving needs of today's biotherapeutic and cell & gene therapy sectors.

After the merger, ProtaGene maintained GeneWerk's site based in Heidelberg near the DKfZ, and serves as a center of excellence for Integration Site Analysis and safety-relevant assays in Cell and Gene Therapy, carrying on the legacy of its predecessor. Moreover, ProtaGene benefits from the continued contributions of key scientists from the founding team who remain with the company. In 2022, ProtaGene opened a brand-new, state-of-the-art laboratory in the U.S. in the Burlington Bio Center, located within suburban Boston's rapidly growing biotechnology hub. As a result, the cutting-edge technologies pioneered in Heidelberg are now poised to make a significant impact in the United States, the world's largest market for cell and gene therapy.

ProtaGene's services for the gene and cell therapy sectors include the valuable bioanalysis approaches  Integration Site Analysis (ISA), biodistribution and vector shedding as well as numerous CMC offerings for supporting product development. GeneWerk innovations in vector analysis and quality control, off-target analysis of gene editing tools, immune repertoire analysis, and bioinformatic analysis of Next Generation Sequencing (NGS) data are an important part of ProtaGene’s offerings.The methods of these services were developed and adapted to these goals by founding GeneWerk researchers.

For example, one of the company's bioanalysis services, (nr)LAM-PCR-enabled ISA, was developed by one of GeneWerk's founders and became an FDA- and EMA-approved standard procedure for integrational gene therapies safety assessments. This method, together with a sophisticated bioinformatical analysis, was further matured over time for different vector applications, and nowadays requested broadly by biopharma organizations to understand the safety of their drug products.

During gene therapy development, the off-target integration of vectors in the genome may cause adverse effects, such as tumorigenesis. ISA is the key tool to ensure the biosafety of gene therapies by assessing integration profiles and allowing the clonal tracking of the modified cells in vivo. ProtaGene also provides off-target analyses of gene editing tools, such as CRISPR or TALENs, using LM-PCR and S-EPTS methods adapted specially for this task.

Additionally, ProtaGene offers various vector analytical and quality control services that align with FDA and EMA regulations. These analytic methods include the exact determination of the vector copy number and vector stability, the assessment of replication efficacy, and analysis of nucleic acid composition and post translational modifications.

Additionally to laboratory-based services, the company offers bioinformatical services to aid the analysis of NGS data. NGS is a parallel sequencing technology that provides a large-scale and rapid determination of the nucleotide sequence of whole genomes; however, the method generates vast amounts of data, of which analysis is complicated and requires expertise. ProtaGene's bioinformatics team can develop customized data analysis pipelines to test gene therapies.

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