Current projects

Comprehensive molecular diagnosis using whole genome and RNA sequencing of patients with advanced cancers as part of the NCT/DKTK MASTER program led to the identification of cancer-driving NRG1 fusions in a significant proportion of KRAS wild type pancreatic cancers. NRG1 rearrangements drive cancer development through ErbB receptor-mediated signaling pathway activation, as was shown when patients with NRG1-rearranged pancreatic cancer responded to ErbB inhibitor treatment.

NRG1 fusions are very rare but have now been detected in a broad range of malignant diseases. During a Phase II study, we plan to investigate the effectiveness of the pan-Erb inhibitor afatinib in advanced NRG1-rearranged malignant cancers once standard treatment has failed, at a number of centers in Germany. Patients with NRG1-positive tumors who meet the eligibility criteria can take part in the trial and will receive afatinib monotherapy.

Coordinators

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Dr. Christoph Heining
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Prof. Dr. Hanno Glimm
Prof. Dr. med.  Richard  Schlenk
Prof. Dr. med. Richard Schlenk
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Prof. Dr. Stefan Fröhling

Insights into mechanisms of T cell response and resistance in post-treatment multicellular AMPLIFY NEOVAC glioma organoids

The adaptive immune system is able to function as a body’s own defense against malignant cells, hence to fight tumor cells. Here, so-called T cells play a crucial role. In cancer, however, T cells become exhausted and may even act inhibitory on the immune response. Clinical therapies apply so-called immune checkpoint inhibitors (IC), thereby reactivating previously exhausted T cells and hence leading to more effective anti-tumor immune responses.

The majority of diffuse gliomas, particularly malignant brain tumors, which are incurable despite resection, irradiation and chemotherapy, is defined by the so-called IDH1R132H mutation. DKTK scientists have successfully tested an IDH1R132H-based vaccine, which was self-developed, for safety and immunogenicity (i.e. induction of an immune response) in a first-in-human multicenter phase 1 clinical trial that was supported by the DKTK in patients with IDH1R132H-mutated glioma. In the currently recruiting follow-up phase 1 trail AMPLIFY-NEOVAC (NOA21, NCT03893903), this vaccine is combined with an ICI to achieve a sufficient activation of IDH1R132H-specific T cells in the tumor. Tumor tissue that is resected after immunotherapy (IDH1R132H vaccine and Avelumab ICI) start will be analyzed for cellular immune activity of T cells.

Within the AMI2GO consortium, consisting of scientists at DKTK sites in Berlin, Frankfurt, and Heidelberg under the direction of Prof. Michael Platten, Heidelberg, so-called glioma organoids derived from tumor tissue post treatment will be generated and analyzed. Glioma organoids are cultures which, over several weeks, preserve not only the various cell types present in the tumor, such as tumor cells but also stromal and immune cells, but also their three dimensional composition. Thereby, they reflect the patient tumor. In the frame of this project, several potential mechanisms of intratumoral T cell activity under IDH1R132H vaccination and Avelumab ICI will be analyzed in glioma organoids. 

Coordinators

In the multicenter “AMPLIFY NEOVAC” clinical study DKTK investigators explore a combination immunotherapy for treatment of aggressive brain tumors, malignant glioma. The approach is to boost tumor vaccination, previously developed within DKTK, with so-called immune checkpoint inhibitors (ICIs), which have shown impressive therapeutic activity for other tumors by unblocking the patient’s own immune system. In this trial the immunotherapy will be initiated before a planned resection. The aim of the study is to assess efficacy and to analyze intratumoral anti-tumor immune effects of the combined vaccination/ICI treatment using detailed molecular and immunological studies. These analyses are expected to reveal important mechanisms of response and resistance to targeted immunotherapy in brain tumors.

Coordinators

Despite increasing application and success of personalized treatment in medical oncology, little progress has been made in personalized surgical cancer therapy. The ARMANI trial presents the first prospective, randomized trial to evaluate effectiveness and safety of molecular-guided resection in patients with colorectal liver metastasis (CRLM). While CRLM might be removed independently of the liver’s segmental borders, retrospective data favor anatomic resections in the subgroup of patients with a mutation in the RAS oncogene. Therefore, the ARMANI trial will test the hypothesis, if an anatomic resection (AR) improves long-term outcome vs. a non-anatomical resection (NAR) in patients undergoing surgery for RAS-mutated CRLM. The trial will be carried out among 11 high-volume centers of hepato-biliary surgery in Germany. A total of 240 patients will be enrolled and randomized in a 1:1 ratio to undergo an AR vs. NAR. The primary endpoint is intrahepatic disease-free survival (iDFS). In addition, the study will provide important data on perioperative outcomes and quality of life for both surgical techniques. Given the trend among liver surgeons to aim for parenchymal-sparing operations to preserve liver parenchyma, a positive trial will be practice changing and present the first piece of high-level evidence on benefits of personalized surgical therapy guided by the tumor’s mutational profile in patients with CRLM.

Coordinators

Glioblastomas are particularly aggressive, and generally incurable, brain tumors. The CAR2BRAIN trial treats patients with an HER2-positive glioblastoma who have suffered a relapse. The research team uses genetically modified natural killer cells (NK cells) with a chimeric antigen receptor (CAR) that enables them to detect the HER2 antigen and selectively attack glioblastoma cells. Since the HER2 antigen is often formed by glioblastoma cells but is not detected in healthy brain tissue, it makes a good target for cellular immunotherapy.

The NK cells are injected into the edge of the surgical cavity during the resection operation. The idea is that they will attack any remaining tumor cells directly and also activate the patient’s own immune system against them. In the trial’s expansion cohort, CAR NK cells will also be repeatedly administered into the resection cavity via a reservoir and catheter. The DKTK’s ‘upgrade project’ will enable a detailed characterization of the immune architecture changes triggered by the CAR NK cell therapy in the blood, reservoir fluid and tumor tissue. In addition, the immune response produced by the CAR NK therapy alone will be compared with the result of a combined therapy that also involves immune checkpoint blockade.

Coordinators

Clonal hematopoiesis is a hallmark of hematologic malignancy, but can also be seen in healthy elderly people. This so-called “clonal hematopoiesis of indeterminate potential” (CHIP) is considered as a risk factor for stem cell-driven hematological diseases, including the myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In this project, DKTK scientists join forces to investigate the role of the bone/bone marrow niche in the evolution of CHIP in elderly patients. The aim of the interdisciplinary study is to comprehensively characterize all components of the stem cell niches in the bone marrow in blood-healthy elderly people and patients with MDS/AML. For this purpose, an extensive collection of biosamples from the BoHemE study (Bone and Hematology in the Elderly) is available. With the help of high-throughput technologies, the CHOICE team will trace the molecular and cellular changes in the hematological compartment and the bone marrow microenvironment in CHIP towards MDS/AML. The researchers aim to define factors and key mechanisms that drive clonal hematopoiesis and malignant evolution of the mutant blood stem cells. The project also aims to elucidate the relationship between bone health and impaired hematopoiesis. Functional investigations using patient-derived xenograft models and 3D cell culture models are planned to evaluate the impact of an altered microenvironment on stem cell clonal evolution. The findings from the CHOICE project could help to better predict and perhaps prevent the transformation of a pre-leukemic clone to leukemia in CHIP patients.

Coordinators

A particularly aggressive form of breast cancer is the so-called triple negative breast cancer (TNBC). Patients with this type of tumor usually receive treatment with chemotherapy before surgical removal. While in some cases this treatment sequence leads to a massive reduction in the size of the tumor, it offers little or no benefit to other patients. In the past, attempts have been made to identify subgroups of TNBC based on RNA sequencing that respond differently to chemotherapy. However, these postulated groups are still not clinically applied in the diagnostic routine. 

A new method to classify malignant tumor diseases is the analysis of genome wide DNA methylation. DNA methylation is a dynamic modification of genetic information that can influence gene activity. By using artificial intelligence, complex patterns can be recognized in the DNA methylation profile of tumors, which can provide information about the origin of a tumor cell. In recent studies, new, prognostically relevant tumor subgroups have been found, particularly in the area of brain tumors. 

In cooperation with the German Breast Group (GBG), the extensive analysis of the DNA methylation profile of 400 patients from the GeparOcto (G8) study will be used to identify possible new subclasses of TNBCs and evaluate their significance in terms of predicting the response to chemotherapy. This analysis will be complemented by RNA sequencing in order to be able to make a comparison with the groups postulated so far. 

Coordinators

Screening tumor tissue for genetic alterations allows clinicians to identify patients who most likely will benefit from targeted therapy. EXLIQUID – exploiting liquid biopsies to advance cancer precision medicine – investigates the potential of additional non-invasive tools for guiding treatment decisions and for monitoring of cancer patients. 

The term “Liquid biopsies” (LBs) refers to non-invasive analysis of tumor-derived circulating material such as cell-free DNA in blood samples from cancer patients. Although recent technological advances allow sensitive and specific detection of LB biomarkers, only few LB assays have found their way into clinical routine. EXLIQUID is a DKTK-wide joint funding project that aims at establishing LBs as a minimally-invasive tool for the analysis of molecular alterations in cell-free tumor DNA (ctDNA). To this end, a multicenter repository of high-quality LB samples will be established from patients participating in MASTER and local molecular tumor boards (MTB), in which DNA profiles from tumor tissue are used to guide targeted therapies. In EXLIQUID, LB assays for early prediction of therapy efficacy will be developed based on the analysis of tumor mutant variants and tumor-specific DNA methylation patterns in the ctDNA from these patients. 

By bringing together LB experts from all DKTK partner sites and exploiting the diversity of their particular expertise, complementary skills and technologies, the EXLIQUID consortium addresses the challenges of translating LBs into the clinic. The DKTK structure enables EXLIQUID to be in a unique position to identify liquid biomarkers also in less common tumor types, thereby increasing the number of patients who can benefit from these approaches. 

In addition to its scientific aims, EXLIQUID is building a valuable precision oncology cohort and LB platform, which will be available for future collaborative research studies within the DKTK and beyond.
 

Coordinators

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Dr. Dr. Christof Winter
Institute of Clinical Chemistry and Pathobiochemistry, Klinikum rechts der Isar, Technical University of Munich
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Prof. Dr. Ingeborg Tinhofer-Keilholz
Klinik für Radioonkologie und Strahlentherapie Charité - Universitätsmedizin Berlin

Starting with the treatment of patients with melanoma, immunomodulation by immune checkpoint inhibitors (ICI) has revolutionized cancer therapy in both palliative and adjuvant settings. Since at best half of the treated patients experience durable clinical benefit, combinatorial ICI protocols have been introduced, resulting in improved efficacy but unfortunately also increased toxicity. 

Recently, in the IMMUNED study, a double-blind, randomized, placebo-controlled trial testing PD-1 blockade by nivolumab alone or in combination with concurrent CTLA-4 inhibition by ipilimumab in patients with stage IV melanoma without evidence of disease, we demonstrated a statistically significant and clinically meaningful benefit for the combination of nivolumab plus ipilimumab, which however had significantly more adverse events. A better understanding of the immunological characteristics of patients who already benefit from PD-1 inhibition alone and those who require combined PD-1 and CTLA-4 blockade would allow appropriate patients to be spared the additional side effects of the combination therapy.

In this funded project, we will conduct an integrative study combining genomic, transcriptomic and spatial proteomic analyses of tumor tissue samples with analyses of immunological and tumor characterizing biomarkers as well as clinical data of patients from the IMMUNED study to develop a clinically applicable prediction model for patient outcomes to the different forms of ICI-based immunotherapy.

Coordinators

Strategic initiative: Immune responses to SARS-CoV-2 and the tumor in cancer patients with COVID-19 - implications for clinical outcomes

Certain tumor patients may have an increased risk of serious illness and mortality following a SARS-CoV-2 infection, as the immune system of most cancer patients is modified by the tumor. However, it is not yet clear how the tumor- or therapy-related changes in the patient's immune system impact the course of the infection. Moreover, cancer patients may develop fundamentally different humoral and cellular immune responses after convalescence from SARS-CoV-2 infection as compared to people without a malignant disease. 

In this pilot study, four DKTK sites (Freiburg, Essen/Düsseldorf, Heidelberg and München) have joined forces to cooperatively investigate the immunological characteristics of previously collected samples from tumor patients with concomitant SARS-CoV-2 infection. The study will use the special immunological expertise of each center. Furthermore, the sites will work closely together to harmonize biobank structures and integration of clinical data for these samples. This pilot project will provide the foundation for in-depth immunological knowledge throughout Germany and new insights into the clinical management of patients with cancer and concomitant COVID-19 infection.

Coordinators

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Dr. med. Khalid Shoumariyeh

Analysis of neoantigen distribution, presentation and recognition by vaccine-induced specific T cells

Acute lymphoblastic leukaemia (ALL) is the most common malignancy in children. Reducing the risk of relapse in patients with ALL is an urgent clinical need. T cells are potent effectors against leukaemic blasts and these immune responses can be induced or enhanced by specific peptide vaccination. The feasibility and toxicity of patient-specific peptide vaccination in patients with relapsed ALL has already been investigated within the DKTK project IVAC-ALL-1. After vaccination with individualised peptides, it could be shown that specific T cell responses were induced. In the IVAC-AN project, the T cell responses induced by the peptide vaccination will now be analysed and characterised in more detail: The investigation of the ability of these induced T cells to recognise and destroy the tumour cells is the main focus here. In addition, the T cell receptor genes will be sequenced in order to be independent of the limited T cell clones available for further investigations. Furthermore, TCR-transgenic T cells could be generated for an innovative T cell transfer therapy. The analysis of the sequencing data sets with respect to different mutation spectra and/or dysregulated signalling pathways will help to potentially predict relapse and to identify resistance and immune evasion mechanisms that may serve as potential new (immune)-therapeutic targets. Mass spectrometry analysis will be used to investigate the presentation of tumour-specific neoantigens on blast HLA molecules.

Coordinators

Distributed IT Infrastructure for Multicenter Cohort Analysis in Imaging

The Joint Imaging Platform aims to introduce a technical infrastructure which enables modern and decentralized research in the field of imaging within DKTK. The main focus is on using and evaluating modern machine learning methods for oncological (medical) research projects. In line with CCP-IT and RadPlanBio, JIP also constitutes a strategic initiative within DKTK. The common infrastructure will strengthen the cooperation between the participating hospitals as well as multicenter studies.

Imaging procedures within radiology and nuclear medicine play an increasingly important role in cancer research, both in diagnostics and treatment monitoring of oncological diseases. This field is developing constantly and quickly. The enormous progress in the evolution of artificial intelligence also leads to considerable development in radiological research. The automatic analysis of image data, such as tumor characterization by means of Radiomics, enables the extraction of the most diverse and highly complex information. Afterwards, this information can be correlated with clinical data in order to obtain new findings regarding diseases or even to evaluate the individual treatment situation (Precision Medicine).

In this context, the JIP complies with the highest data protection requirements as it focuses on the distribution of processing methods (algorithms) instead of personal data. The local image data are protected with a state-of-the-art encryption system and are stored within the clinical IT infrastructure of the individual locations at any time. In case data exchange might be necessary within the context of multicenter studies, this can be done – upon the patients‘ agreement - in a pseudonymized way.

More information can be accessed via the website of the "Joint Imaging Platform".

Coordinators

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Prof. Dr. Heinz-Peter Schlemmer
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Prof. Dr. med. Dr. rer. nat. Dipl.-Bioinf.​ Jens Kleesiek
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Prof. Dr. Klaus H. Maier-Hein
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Dr. Marco Nolden

In healthy cells, a number of different processes ensure that damage or mutations to DNA are repaired efficiently. In cancer cells of various tumor entities, however, genes whose products are involved in one of these repair processes can also suffer somatic mutation. These cells then lose some of their DNA repair ability.

If it is the homologous recombination repair system that is affected in this way, the cells are particularly sensitive to a group of drugs called Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors). PARP inhibitors prevent cancer cells from being able to repair themselves, e.g. as a result of DNA damage caused by chemotherapy treatments, and are already used to treat a number of different types of cancer. One such form of acquired sensitivity to a particular group of drugs is called synthetic lethality. 

However, we do not know all the genes or mutations involved in synthetic lethality where PARP inhibitors are concerned. Other biological processes besides mutations, such as hypermethylation of a gene promoter involved in homologous recombination, may contribute to their inactivation. This means that it is not possible using current technical methods, including high-throughput technologies, to systematically identify all the causes of loss of homologous recombination function. On the other hand, these methods can identify a large number of ‘passenger’ mutations that arise following the repair defect. We have developed an integrated genomic biomarker that can detect the fingerprint of this repair defect on the genome of tumor cells with the help of pattern recognition, thereby increasing precision levels when detecting DNA repair defects. Subsequently, we designed a clinical trial in which patients who have tested positive with this biomarker, are treated with a synergistic combination of a PARP inhibitor and matched drug.

In future, as well as conducting a broad, in-depth genomic characterization of the samples from these treated patients, we hope to (i) gain a better understanding of the biological process of DNA repair via homologous recombination, (ii) improve the precision of our biomarker, (iii) improve predictions of the effectiveness of synthetic lethality drugs in DNA repair defect cases, (iv) investigate resistance development mechanisms to these drugs and prevent them occurring in patients, and (v) find new synergistic therapies.​

Coordinators

Dr.  Claudia  Ball
Dr. Claudia Ball
Dr. Dr.  Daniel  Hübschmann
Dr. Dr. Daniel Hübschmann
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Prof. Dr. Hanno Glimm
Dr. med.  Sebastian  Wagner
Dr. med. Sebastian Wagner
Universitätsklinikum Frankfurt Medizinische Klinik II, Hämatologie/Onkologie
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Prof. Dr. Stefan Fröhling
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Prof. Dr. Thomas Kindler
Universitäres Centrum für Tumorerkrankungen Mainz (UCT Mainz) Universitätsmedizin Mainz

The DKTK project 'Molecular Stratification Program' at the National Center for Tumour Diseases (NCT) in Heidelberg focuses on customized therapies. The term 'stratification' refers to the initiative to assign patients with the same initial diagnosis to subgroups according to molecular results in order to be able to offer them a tailored therapy. The project promotes the development of a central database containing gene defects and changes in gene activity of tumour cells. The tumour profiles will help hospitals to tailor therapy for individual patients.

Coordinators

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Prof. Dr. Hanno Glimm
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Prof. Dr. Stefan Fröhling

In this project, we aim to understand PET/CT-based imaging features and their molecular and clinical correlates pre/post therapy in gastroesophageal junction (GEJ) adenocarcinoma. In the DKTK-funded MEMORI trial we evaluated PET-directed chemo- (CTX) or salvage radiochemotherapy (CRT) and assembled sequential high-quality tumor tissue at PET/CT imaging time points pre/post therapy. The fully recruited trial, met its primary endpoint of improved negative surgical margins (R0 rate) upon salvage intensified CRT not responding to standard neoadjuvant CTX determined by PET response 14 days after CTX initiation. Salvage CRT also led to a highly increased rate of pathologic complete remissions (pCR) suggesting high local activity of CRT. However, an important result from the trial was distant recurrence in a subgroup of patients despite high R0 resection and pCR rates. Thus, current standard-of care PET/CT or histological diagnostics do not identify high- risk patients with bad outcome and their distinguishing tumor features remain unknown.

We here aim to investigate molecular subtypes and tumor metabolism patterns in the MEMORI patient cohort. We will focus on understanding therapy-induced molecular dynamics. We will correlate these findings with PET-CT derived metabolic and anatomical imaging data using standard (SUVmax/mean) and advanced (radiomics) techniques leveraging the infrastructure provided by the Joint Imaging Platform (JIP) to perform an integrated analysis of clinical, molecular and imaging data. The available clinical and multimodal imaging data combined with available tumor tissue before, during and after neoadjuvant therapy are a unique opportunity to address fundamental questions of imaging and tissue- based features in tumor metabolism, heterogeneity and therapy response. 

Coordinators

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Prof. Dr. Wolfgang Weber
Klinikum rechts der Isar Nuklearmedizinische Klinik und Poliklinik

Among other things, cancers are caused by a malfunction of the immune system. Therefore, targeting the immune response is a promising approach to treat tumor diseases. So-called immune checkpoint inhibitors, for example PD-L1 blocking antibodies, offer an option for this. They generate an efficient systemic immune response against tumors and, despite systemic application, are effective against many different types of solid cancer. Further research will be conducted to explore the potential for combining ICI with therapies that specifically target cancer cells. In the underlying CRAFT study (Continuous ReAssessment with Flexible exTension trial), five different agents are being combined with PD-L1 blockade. The aim is to improve the efficacy of cancer immunotherapy and to overcome treatment resistance. As part of the associated MIMETIC project (MIMETIC = Monitoring the immune modulating effects of combinatorial targeted and immune checkpoint inhibitor treatment), comprehensive monitoring of the immune status of the study participants is taking place. Both genetic and immunological factors in the tumor as well as in the periphery will be monitored, which will allow to draw conclusions about the effects of the various therapy options. By combining the complementary clinical, scientific and methodological expertise of the three DKTK partner sites in Dresden, Heidelberg and Frankfurt/Mainz, tumor and blood cells will be evaluated to characterize cancer and immune cells phenotypically and functionally. The use of state-of-the-art scientific methods such as plasmaproteomics, multiparameter flow cytometry, multispectral imaging and T-cell receptor sequencing will help to obtain a comprehensive understanding of the immunomodulatory properties of combined targeted immunotherapy.

Coordinators

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Prof. Dr. Tobias Bopp
Institut für Immunologie und Forschungszentrum für Immuntherapie (FZI) Universitätsmedizin Mainz

Patients with advanced cancers, for whom all standard therapy options have been exhausted, today are eligible for a broad genetic characterization of their tumor disease and - where feasible - targeted, tailor-made therapy, this takes place in so-called molecular tumor boards (MTB). MTBs have been implemented at all major cancer centers in the last few years. A persistent problem, however, is the lack of harmonization of these structures across individual locations and the hitherto missing aggregation of genetic and clinical data for scientific purposes. The Molecular Tumor Board Alliance (MTBA) of the German Cancer Consortium (DKTK) has set itself the goal of addressing these aspects in a joint effort of all DKTK partner sites by developing common binding standards for patient inclusion, genetic evaluation and visualization, therapy recommendation and follow-up. The unique collection of DKTK MTB data sets are harmonized and standardized by the MTBA and made scientifically and clinically usable via a data protection-secure cross-site query function.

Coordinators

Clinical development of lead NEOantigen-specific T cell receptors for Adoptive T cell Therapy of solid tumors (NEO-ATT)

Targeting cancer mutations by reactivating neoepitope-specific T cells using checkpoint blockade has shown therapeutic success in solid cancers with high mutational load but is hampered in patients with tumors carrying lower numbers of mutations. Thus, for less immunogenic tumors such as pancreatic ductal adenocarcinoma (PDA) and glioblastoma, targeting mutations by T cell receptor (TCR) gene therapy may be a more appropriate strategy. Even though adoptive therapy using engineered T cells is still looked upon skeptically, especially in Europe, the overwhelming success of chimeric antigen receptor (CAR) T cell therapy in the USA has provided clear-cut proof of concept for clinical and commercial viability of such strategies.

Through third party funding from the German Cancer Aid Priority Program Translational Oncology, our team of DKTK partners has identified a series of HLA-A*02:01 restricted TCRs against various recurrent and patient-individual mutations. Based on these findings, in this follow-up research project neoepitopes, e.g. derived from activating mutations recurrent in PDA, glioblastoma and melanoma, will be analysed for targeting by TCR-engineered T cells. Based on in vivo anti-tumor efficacy testing in clinically relevant models, a lead TCR will be selected for GMP-compliant retrovirus production. Manufacturing of T cell products in closed GMP-manufacturing systems are currently established and will facilitate first-in-human testing.

In addition, we will explore SEREX antigens for recognition by MHC class II restricted CD4+ T cells and obtain pre-clinical proof of concept for the combinatorial use of mutation-specific CD8+ T cells and tumor-specific CD4+ T helper cells. Tumor-specific CD4+ T cell help is not only important for an optimal CD8+ T cell effector response, but also for countering tumor immune escape through loss of HLA class I-expression and/or deficiencies in antigen processing, two immune-editing features potentially encountered in human cancers.

Coordinators

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Prof. Dr. Rienk Offringa
Molecular Oncology of Gastrointestinal Tumors (G180) Deutsches Krebsforschungszentrum (DKFZ)
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Prof. Dr. Thomas Blankenstein
Charité - University Medicine Berlin at the Max-Delbrück-Center for Molecular Medicine AG Molekulare Immunologie und Gentherapie

Image-based subtyping of locally advanced pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because the tumor is often already at an advanced stage when first diagnosed and because of resistance to conventional chemotherapy treatments. The genome, transcriptome and proteome of these tumors are highly heterogeneous. This heterogeneity is reflected in a complex tissue architecture with different molecular phenotypes: the classic phenotype with a somewhat better response rate, and the particularly aggressive quasi-mesenchymal phenotype.

There are currently no reliable biomarkers to differentiate between these subtypes in routine clinical practice. This again is partly because of the high degree of heterogeneity, which makes it harder to ensure representative sampling and draw histopathological and molecular conclusions. Medical imaging provides information on total tumor volume. Recent developments in the field of machine learning (e.g. radiomics) are showing promising results in terms of non-invasive tumor characterization and risk stratification based on medical imaging. Translational development and testing of these kinds of prognostic models require a standardized data matrix.

The NEOLAP phase II clinical trial (NCT02125136) is one of the biggest randomized prospective trials that aims to evaluate intensified neoadjuvant chemotherapy in locally advanced PDAC. The image datasets, tumor samples and clinical information collected prospectively for the NEOLAP trial offer a unique opportunity to develop and test the image-based algorithms mentioned above.   

Coordinators

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Prof. Dr. med. Dr. rer. nat. Dipl.-Bioinf.​ Jens Kleesiek
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Prof. Dr. Rickmer Braren
Institute of Diagnostic and Interventional Radiology Technische Universität München Klinikum rechts der Isar

Pediatric low-grade gliomas (pLGGs), including pilocytic astrocytomas (PAs), are the most common childhood brain tumors. While the overall survival rate is very good, progression-free survival, especially in subtotal resection cases, is low. Chemotherapy is currently the standard treatment, but it is associated with secondary damage. Moreover, tumor-associated morbidity is particularly high in cases that cannot be fully resected and do not respond well to conservative therapy. Despite the very good overall survival rate, therefore, there is a need to establish new therapy approaches to significantly improve the quality of life of patients with this chronic disease. The researchers working on the DKTK’s Next Gen LOGGIC project aim to generate preclinical data in collaboration with the LOGGIC pLGG trial that will form the basis for next-generation clinical trials. Working with the Berlin, Düsseldorf, Freiburg and Heidelberg sites, they are investigating the signaling pathways, the proteome and the response to novel low-molecular substances in pLGG models and primary tumors. Integration with the molecular and clinical data from LOGGIC Core and the ongoing clinical trial for pLGGs (LOGGIC trial) ensures the translational value of the preclinical data.

Coordinators

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Prof. Dr. Till Milde

Well-conducted clinical trials have demonstrated that vitamin D supplementation reduces cancer mortality and enhances survival of colorectal cancer patients in particular. Vitamin D supplementation could therefore be a promising approach for supportive cancer therapy, but the underlying mechanisms of action of vitamin D are only partially understood. Also, all previous clinical trials applied uniform doses of vitamin D, without paying attention to the strongly divergent needs of patients according to their baseline vitamin D status and weight. The coordinator of this project currently conducts a new clinical trial funded by the World Cancer Research Fund, called VICTORIA, which will, for the first time, evaluate the impact of a personalized vitamin D supplementation (PEVIDS) dose on adverse health outcomes among 456 colorectal cancer patients, of whom half will receive PEVIDS and half placebo (which is no active drug).

In the DKTK funded PEVIDS project, we will assess the impact of PEVIDS on several important molecules of the immunome (sum of all immunologically active molecules) and proteome (sum of all proteins) of colorectal cancer patients in multiple biomaterials (blood, urine, and stool) to identify potential mechanisms of PEVIDS effects. The research will be conducted in interdisciplinary collaboration by researchers from three DKTK sites with complementary expertise in cancer prevention, immunology, and proteome analyses.

Coordinators

The multi-center first-user study to investigate the safety, tolerance and effectiveness of the bispecific PSMAxCD3 antibody CC-1 in patients with prostate cancer is being carried out at University Hospital Tübingen in its Clinical Collaboration Unit Translational Immunology, and at other DKTK sites in Germany.

Bispecific antibodies are protein molecules with two different binding sites. In the case of the bispecific PSMAxCD3 antibody CC-1, one binding site addresses the prostate-specific membrane antigen (PSMA), which presents on the surface of aggressive prostate cancer cells. The other arm binds to a protein that is responsible for activating defense cells called T cells. When the antibody binds to the two binding sites, it activates the body’s immune response. In addition, CC-1 has a special characteristic: it also binds to the tumor’s blood vessels, creating a dual anti-tumor effect.

A serious side effect of the bispecific antibodies currently available is excessive activation of the immune system. This causes cytokine release syndrome (CRS). CRS can lead to a wide range of symptoms, including in particular fever and cardiovascular problems. When CRS occurs, the patient is usually treated with tocilizumab, an antibody that lessens the excessive immune system response.

For the study, the CC-1 antibody was optimized to minimize the risk of an unwanted immune activation. In addition, patients participating in the trial are given tocilizumab as a preventative measure to start with, in order to prevent CRS occurring in the first place.

Coordinators

Prof. Dr. med.  Richard  Schlenk
Prof. Dr. med. Richard Schlenk

Anti-angiogenic agents are a key element of drug therapy for patients with metastatic colorectal cancer (mCRC). Despite intensive efforts over recent years, there is still a lack of biomarkers that can predict whether these medicines will be effective. Complex interactions between the tumor cells and the surrounding stroma have made it harder to identify suitable biomarkers.

The aim of the RAMTAS study-related research project is to identify a molecular signature in patients with mCRC that can predict a response to anti-angiogenic therapy. To this end, researchers are analyzing tumor and blood samples from a phase II clinical trial (RAMTAS, NCT03520946) that was held at Arbeitsgemeinschaft Internistische Onkologie (AIO) that investigates the use of a monoclonal antibody against vascular endothelial growth factor receptor 2 (VEGFR-2). This receptor plays a key role in tumor neoangiogenesis and is an attractive target structure for modern molecular drugs.

There is a particular focus on the analysis of somatic gene mutations, gene expression profiles and post-translational protein modifications. In addition, IT-assisted machine learning and data mining make it possible to increase our understanding of the complex interactions between the individual profiles and to explore and validate the prognostic value regarding the effectiveness of the anti-angiogenic agent. 

Coordinators

The greatest challenge in modern cancer therapies is the emergence of therapy-resistant cancer cells after seemingly successful initial treatment. Single resistant cells can sometimes trigger tumor recurrence and metastasis years after initial treatment, which is typically more aggressive and even more difficult to treat than the initial tumor. Acute myeloid leukemia (AML) is a particularly aggressive blood cancer with a very high relapse rate associated with a subsequent very poor prognosis. The DKTK RiskY-AML consortium brings together oncologists, cancer biologists and computer scientists from six DKTK sites. It will use a range of novel single-cell technologies and data analysis tools to identify the molecular mechanism by which AML cells escape current therapies. RiskY-AML will then use the gained high-resolution insights into the molecular landscape of resistant AML cells to develop new predictive biomarkers and novel therapeutic options to prevent or overcome resistance and relapse in AML patients. 

Coordinators

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Prof. Dr. Andreas Trumpp

The SoraTram trial is a basket study designed to evaluate a new concept for treating a wide range of tumors with kinase-inactivating BRAF mutations. The BRAF enzyme is an important link in the RAS/RAF/MEK/ERK signaling chain that promotes cell division and, as a result of mutations, is present in a hyperactive state in many tumors. Drugs that inhibit the hyperactive oncoprotein BRAF V600E are already used to treat a number of cancers. The sequencing of tumor genomes has also identified increasing numbers of non-V600E mutations. In most cases, the clinical significance of these and their susceptibility to drugs have not yet been described. A sub-group of these non-V600E BRAF mutations inhibit the enzyme activity of the BRAF kinase. Paradoxically, however, these inactive BRAF mutants activate the ERK signaling chain and stimulate the onset of tumors. Preclinical models have shown that sorafenib, a drug that was approved several years ago for the treatment of kidney and liver cancer, can block the paradoxical effect of kinase-inactive BRAF mutants. The combination of sorafenib and the inhibitor trametinib is even more effective at blocking tumor growth. The effectiveness of this SoraTram combination has already been demonstrated in an index case with a metastatic melanoma. (1) 

The SoraTram study, which is planned to run at all DKTK sites, aims to

• identify patients in the DKTK MASTER network with tumors harboring non-V600 BRAF mutations 

• characterize mutations in terms of their susceptibility to BRAF, CRAF and MEK inhibitors and combinations of these

• treat 30 DKTK MASTER patients harboring non-V600 BRAF mutations that respond to CRAF/MEK inhibition following in vitro testing, with sorafenib and trametinib in a prospective multicenter Phase II trial

Comprehensive tumor sequencing in the DKTK network, especially through the MASTER program, is currently identifying many novel BRAF mutations whose significance remains unclear. These will be validated and verified during the study, both in terms of their kinase-inactivating potential and their oncogenic potential and susceptibility to pharmacological intervention. The cataloging of all non-V600E mutations can then be used for personalized therapy recommendations.

(1) Hoefflin R, Geißler AL, Fritsch R, Claus R, Wehrle J, Metzger P, et al. Personalized clinical decision making through implementation of a molecular tumor board – a German single-center experience.  JCO Precision Oncology. 2018; DOI: 10.1200/PO.18.00105 JCO Precision Oncology - published online August 16, 2018

Coordinators