Publications

Redding A, Fonteneau G, Heinrich S, Gaida M, Grabocka E

Cytosolic Phospholipase A2 determines Intercellular Heterogeneity of Stress Granules and Chemotherapy Response

Cancer Discov. 2025

DOI

Möhrmann L, Rostock L, Werner M, Oleś M, Arnold JS, Paramasivam N, Jöhrens K, Rupp L, Schmitz M, Richter D, Uhrig S, Fröhlich M, Hutter B, Hüllein J, Jahn A, Arlt M, Möhrmann EE, Hanf D, Gieldon L, Kreutzfeldt S, Heilig CE, Teleanu MV, Lipka DB, Beck K, Baude-Müller A, Mock A, Jelas I, Rieke DT, Wiesweg M, Brandts C, Boerries M, Illert AL, Desuki A, Kindler T, Krackhardt AM, Westphalen CB, Christopoulos P, Apostolidis L, Stenzinger A, Allgäuer M, Neumann O, Kerle IA, Horak P, Heining C, Grosch H, Schröck E, Hübschmann D, Fröhling S, Glimm H.

Genomic landscape and molecularly informed therapy in thymic carcinoma and other advanced thymic epithelial tumors

Med. 2025

DOI

Kelm N, Kespohl M, Smagurauskaite G, Vales S, Karuppanan K, Mburu P, Thiele A, Pinkert S, Bukur T, Mülleder M, Berndt N, Klingel K, Gaida MM, Bhattacharya S, Beling A.

Assessing customized multivalent chemokine-binding peptide treatment in a murine model of coxsackievirus B3 myocarditis

Basic Res Cardiol. 2025

DOI

Krušič, A, Mencin N, Leban M, Nett E, Perković M, Ugur Sahin U, Megušar P, Štrancar A, Sekirnik R.

Reverse-phase chromatography removes double-stranded RNA, fragments and residual template to decrease immunogenicity and increase cell potency of mRNA and saRNA

Molecular Therapy Nucl Ac. 2025

DOI

Schneider AT, Koppe C, Crouchet E, Papargyriou A, Singer MT, Büttner V, Keysberg L, Szydlowska M, Jühling F, Moehlin J, Chen MC, Leone V, Mueller S, Neuß T, Castoldi M, Lesina M, Bergmann F, Hackert T, Steiger K, Knoefel WT, Zaufel A, Kather JN, Esposito I, Gaida MM, Ghallab A, Hengstler JG, Einwächter H, Unger K, Algül H, Gassler N, Schmid RM, Rad R, Baumert TF, Reichert M, Heikenwalder M, Kondylis V, Vucur M, Luedde T.

A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development

Nat Commun. 2025

DOI

Paolucci M, Nilsson FAM, Duda A, Tusup M, Diken M, Kündig TM, Johansen P.

Intralymphatic Administration of Naked mRNA Induces Allergen-Specific IgG, Promotes Th1 Responses and Reduces Anaphylactic Potential

Allergy. 2025

DOI

Blomain E, Soudi S, Wang Z, Somani A, Subramanian A, Nouth S, Oladipo E, New C, Kenney D, Nemat-Gorgani N, Kindler T, Avedian R, Steffner R, Mohler G, Hiniker S, Chin A, Kalbasi A, Binkley M, Fried M, Gaida M, van de Rijn M, Moding E

Evolutionary Pressures Shape Undifferentiated Pleomorphic Sarcoma Development and Radiotherapy Response

Cancer Res. 2025

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Schorn S, Fritz A, Kaissis G, Gaida MM, Steiger K, Jäger C, Schlitter AM, Braren R, Friess H, Demir IE, Ceyhan GO.

Neural invasion severity is a strong predictor of local recurrence in pancreatic ductal adenocarcinoma

Surgery. 2025

DOI

Background: In pancreatic ductal adenocarcinoma, neural invasion is being increasingly recognized as an unfavorable predictor of patient outcomes. Neural invasion severity seems to have a stronger clinical impact on patient prognosis than neural invasion status alone. Therefore, this study aims to assess the impact of severity of neural invasion on overall survival and disease-free survival in pancreatic ductal adenocarcinoma.

Materials: To assess the impact of intrapancreatic neural invasion severity, tumor specimens resected from patients with pancreatic ductal adenocarcinoma between 2007 and 2014 were systematically re-evaluated, and neural invasion severity was determined using the standardized neural invasion severity score.

Results: In our cohort (n = 216), an increased neural invasion severity score was associated with markedly shorter overall survival in pancreatic head ductal adenocarcinoma (neural invasion severity score low: 22.8 months vs neural invasion severity score high: 17.6 months: P = .001). An external European validation cohort confirmed these results and showed significantly better survival of patients with lower neural invasion (20.5 vs 15.4 months, P = .026). The disease-free survival time was also substantially decreased in patients with pancreatic head pancreatic ductal adenocarcinoma and increased neural invasion severity (neural invasion severity score low: 19.1 months vs neural invasion severity score high: 10.4 months; P = .004). Moreover, the neural invasion severity score was an important independent factor influencing overall survival (hazards ratio 1.024, P = .04) and disease-free survival (hazards ratio 1.03, P = .01) using an adjusted Cox proportional hazards model. Importantly, higher neural invasion severity score leads to significantly more and earlier local recurrence than to distant tumor recurrence.

Conclusion: Neural invasion severity is a powerful independent factor influencing overall survival and local recurrence in patients with pancreatic ductal adenocarcinoma. Therefore, individuals with high neural invasion severity score values should be regarded as a specific subgroup of pancreatic ductal adenocarcinoma patients and may benefit from more tailored postoperative oncologic therapy.

Lopez J, Powles T, Braiteh F, Löwer M, et al.

Autogene cevumeran with or without atezolizumab in advanced solid tumors: a phase 1 trial

Nature Med. 2025

DOI

Benderski K, Schneider P, Kordeves P, Fichter M, Schunke J, De Lorenzi F, Durak F, Schrörs B, Akilli Ö, Kiessling F, Bros M, Diken M, Grabbe S, Schattenberg JM, Lammers T, Sofias AM, Kaps L.

A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing

Pharmacol Res . 2024

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Gleue L, Graefen B, Voigt M, Schupp J, Schneider D, Fichter M, Kuske M, Mailaender V, Tuettenberg A, Helm M.

Dual Centrifugation-Based Screening for pH-Responsive Liposomes

ChemMedChem. 2024

DOI

Lüttman F F, Kim K-P, Kim J.

Spliceosomal repression: unleashing human cell totipotency

Signal Transduction and Targeted Therapy, 2024

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Schramm E, Becker V, Palagi I, Müller M, Rösler T, Durak F, Ebering A, Karram K, von Stebut E, Schmeisser MJ, Waisman A.

Constitutive expression of the deubiquitinating enzyme CYLD does not affect microglia phenotype or function in homeostasis and neuroinflammation

J Mol Med (Berl). 2024

DOI

The deubiquitinating enzyme CYLD negatively regulates NF-κB signaling by removing activating ubiquitin chains from several members of the NF-κB pathway. Thereby, CYLD is critical for the maintenance and differentiation of various immune cells. Despite the importance of the NF-κB pathway in microglia regulation, the role of CYLD in microglia has not been investigated so far. In this study, we investigated whether CYLD in microglia can protect against neuroinflammation using a newly generated conditional mouse strain (Rosa26-Cyld-tdTomato) that allows cell type-specific CYLD overexpression. Here, we show that overexpression of CYLD in microglia did not alter microglia numbers or microglia morphology in different brain regions. Additionally, CYLD overexpression did not modify the microglial response to LPS-induced neuroinflammation or the disease severity in experimental autoimmune encephalomyelitis (EAE). Finally, also immune cell infiltration into the CNS during EAE and under steady state conditions remained unaffected by microglial CYLD overexpression. Our findings suggest that CYLD overexpression does not alter microglial function, and thus does not represent a viable therapeutic strategy in neuroinflammatory conditions. This study highlights the complexity of ubiquitin-mediated signaling in neuroinflammation and the need for cell-type-specific investigations. The Rosa26-Cyld-tdTomato mouse model offers a valuable tool for studying CYLD's role across various tissues and cell types. KEY MESSAGES: Novel mouse strain for cell type-specific overexpression of the deubiquitinating enzyme CYLD. CYLD overexpression in microglia did not alter microglia numbers or morphology in the steady state. CYLD overexpression in microglia did not protect mice from LPS-induced neuroinflammation or EAE. CYLD overexpression in microglia did not influence their gene expression during neuroinflammation.

Bresadola L, Weber D, Ritzel C, Löwer M, Bukur V, Akilli-Öztürk Ö, Schuster C, Gargano A, Becker J, Mehanna H, Schrörs B, Vascotto F, Sahin U & Kong, A.

Temporal evolution and inter-patient heterogeneity in primary and recurrent head and neck squamous cell carcinoma

BJC Reports volume 2, Article number: 62 (2024)

DOI

Muik A, Quandt J, Lui BG, Bacher M, Lutz S, Grünenthal M, Toker A, Grosser J, Ozhelvaci O, Blokhina O, Shpyro S, Vogler I, Salisch N, Türeci Ö, Sahin U.

Immunity against conserved epitopes dominates after two consecutive exposures to SARS-CoV-2 Omicron BA.1

Cell Rep. 2024

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Muik A, Quandt J, Lui BG, Bacher M, Lutz S, Grünenthal M, Toker A, Grosser J, Ozhelvaci O, Blokhina O, Shpyro S, Vogler I, Salisch N, Türeci Ö, Sahin U.

Immunity against conserved epitopes dominates after two consecutive exposures to SARS-CoV-2 Omicron BA.1

Cell Rep. 2024

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Mohamed S, Barlemann A, Steinle V, Nonnenmacher T, Güttlein M, Hackert T, Loos M, Gaida M, Kauczor H, Klauss M & Mayer P.

Performance of different CT enhancement quantification methods as predictors of pancreatic cancer recurrence after upfront surgery.

Sci Rep 14, 19783 (2024)

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Muhammad S. Alam M, Gaida M, Witzel H, Otsuka S, Abbasi A, Guerin T, Abdelmaksoud A, Wong N, Cam M, Kozlov, S, Ashwell J.

TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function

Cell Reports Medicine, August 22 (2024)

DOI

Ahrberg Y, Dallmann J, Freitag J, Hassan A, Jung C, Kiefer J, Muralidharan AM, Peter M, Beck JD..

CIMT 2024: Report on the 21st Annual Meeting of the Association for Cancer Immunotherapy

Hum Vaccin Immunother. 2024

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Schneider P, Zhang H, Simic L, Dai Z, Schrörs B, Akilli-Öztürk Ö, Lin J, Durak F, Schunke J, Bolduan V, Bogaert B, Schwiertz D, Schäfer G, Bros M, Grabbe S, Schattenberg JM, Raemdonck K, Koynov K, Diken M, Kaps L, Barz M

Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma

Advanced Materials 2024

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Yıldız A, Hasani A, Hempel T, Köhl N, Beicht A, Becker R, Hubich-Rau S, Suchan M, Poleganov M, Sahin U, Beissert T

Trans-amplifying RNA expressing functional miRNA mediates target gene suppression and simultaneous transgene expression

Molecular Therapy: Nucleic Acids 2024

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Khristenko E, Gaida MM, Tjaden C, Steinle V, Loos M, Krieger K, Weber TF, Kauczor HU, Klauß M, Mayer P

Imaging differentiation of solid pseudopapillary neoplasms and neuroendocrine neoplasms of the pancreas

European Journal of Radiology Open 2024

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Lang F, Sorn P, Suchan M, Heinrich A, Albrecht C, Köhl N, Beicht A, Riesgo-Ferreiro P, Holsträter C, Schrörs B, Weber D, Löwer M, Sahin U, Ibn-Salem J

Prediction of tumor-specific splicing from somatic mutations as a source of neoantigen candidates

Bioinformatics Advances, 2024

DOI PMID

{"time":1718286861047,"blocks":[{"id":"hkK6U-Mb8a","type":"paragraph","data":{"text":"Motivation"}},{"id":"2vwZmW98lz","type":"paragraph","data":{"text":"Neoantigens are promising targets for cancer immunotherapies and might arise from alternative splicing. However, detecting tumor-specific splicing is challenging because many non-canonical splice junctions identified in tumors also appear in healthy tissues. To increase tumor-specificity, we focused on splicing caused by somatic mutations as a source for neoantigen candidates in individual patients."}},{"id":"IZSppkVS5L","type":"paragraph","data":{"text":"Results"}},{"id":"aLWhZAIEw5","type":"paragraph","data":{"text":"We developed the tool splice2neo with multiple functionalities to integrate predicted splice effects from somatic mutations with splice junctions detected in tumor RNA-seq and to annotate the resulting transcript and peptide sequences. Additionally, we provide the tool EasyQuant for targeted RNA-seq read mapping to candidate splice junctions. Using a stringent detection rule, we predicted 1.7 splice junctions per patient as splice targets with a false discovery rate below 5% in a melanoma cohort. We confirmed tumor-specificity using independent, healthy tissue samples. Furthermore, using tumor-derived RNA, we confirmed individual exon-skipping events experimentally. Most target splice junctions encoded neoepitope candidates with predicted major histocompatibility complex (MHC)-I or MHC-II binding. Compared to neoepitope candidates from non-synonymous point mutations, the splicing-derived MHC-I neoepitope candidates had lower self-similarity to corresponding wild-type peptides. In conclusion, we demonstrate that identifying mutation-derived, tumor-specific splice junctions can lead to additional neoantigen candidates to expand the target repertoire for cancer immunotherapies."}},{"id":"0aJrlFpSL7","type":"paragraph","data":{"text":"Availability and implementation"}},{"id":"MSFHxqilTC","type":"paragraph","data":{"text":"The R package splice2neo and the python package EasyQuant are available at https://github.com/TRON-Bioinformatics/splice2neo and https://github.com/TRON-Bioinformatics/easyquant

Mayer P, Hausen A, Steinle V, Bergmann F, Kauczor, H, Loos M, Roth W, Klauss M, Gaida M.

The radiomorphological appearance of the invasive margin in pancreatic cancer is associated with tumor budding

Langenbecks Arch Surg . 2024

DOI

De Sanctis F, Dusi S, Caligola S, Anselmi C, Petrova V, Rossi B, Angelini G, Erdeljan M, Wöll S, Schlitter A M, Metzler T, Steiger K, Borok Z, Bailey P, Bauer A, Halin C, Boschi F, Giugno R, Canè S, Lawlor R, Corbo V, Scarpa A, Constantin G, Ugel S, Vascotto F, Sahin U, Türeci Ö, Bronte V

Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer

Immunity, 2024

DOI

Köhler A, Geiselhöringer AL, Kolland D, Kreft L, Wichmann N, Hils M, Pasztoi M, Zurkowski E, Vogt J, Kübelbeck T, Biedermann T, Schmitz I, Hansen W, Kramer D, Gaida MM, Schmidt-Weber CB, Hoevelmeyer N, Ohnmacht C

The atypical IκB family member Bcl3 determines differentiation and fate of intestinal RORγt+ regulatory T cell subsets

Mucosal Immunol. 2024

DOI

Neuhaus F, Lieber S, Shinkevich V, Steitz AM, Raifer H, Roth K, Finkernagel F, Worzfeld T, Burchert A, Keber C, Nist A, Stiewe T, Reinartz S, Beutgen VM, Graumann J, Pauck K, Garn H, Gaida M, Müller R, Huber M.

Reciprocal crosstalk between Th17 and mesothelial cells promotes metastasis-associated adhesion of ovarian cancer cells

Clin Transl Med 2024

DOI

Background: IL-17A and TNF synergistically promote inflammation and tumorigenesis. Their interplay and impact on ovarian carcinoma (OC) progression are, however, poorly understood. We addressed this question focusing on mesothelial cells, whose interaction with tumor cells is known to play a pivotal role in transcoelomic metastasis formation. Methods: Flow-cytometry and immunohistochemistry experiments were employed to identify cellular sources of IL-17A and TNF. Changes in transcriptomes and secretomes were determined by bulk and single cell RNA sequencing as well as affinity proteomics. Functional consequences were investigated by microscopic analyses and tumor cell adhesion assays. Potential clinical implications were assessed by immunohistochemistry and survival analyses. Results: We identified Th17 cells as the main population of IL-17A- and TNF producers in ascites and detected their accumulation in early omental metastases. Both IL-17A and its receptor subunit IL-17RC were associated with short survival of OC patients, pointing to a role in clinical progression. IL-17A and TNF synergistically induced the reprogramming of mesothelial cells towards a pro-inflammatory mesenchymal phenotype, concomitantly with a loss of tight junctions and an impairment of mesothelial monolayer integrity, thereby promoting cancer cell adhesion. IL-17A and TNF synergistically induced the Th17-promoting cytokines IL-6 and IL-1β as well as the Th17-attracting chemokine CCL20 in mesothelial cells, indicating a reciprocal crosstalk that potentiates the tumor-promoting role of Th17 cells in OC. Conclusions: Our findings reveal a novel function for Th17 cells in the OC microenvironment, which entails the IL-17A/TNF-mediated induction of mesothelial-mesenchymal transition, disruption of mesothelial layer integrity and consequently promotion of OC cell adhesion. These effects are potentiated by a positive feedback loop between mesothelial and Th17 cells. Together with the observed clinical associations and accumulation of Th17 cells in omental micrometastases, our observations point to a potential role in early metastases formation and thus to new therapeutic options.

López-Gil JC, García-Silva S, Ruiz-Cañas L, Navarro D, Palencia-Campos A, Giráldez-Trujillo A, Earl J, Dorado J, Gómez-López G, Monfort-Vengut A, Alcalá S, Gaida M M, García-Mulero S, Cabezas-Sáinz P, Batres-Ramos S, Barreto E, Sánchez-Tomero P, Vallespinós M, Ambler L, Lin M-L, Alexandra Aicher A, García de Paredes A G, de la Pinta C, Sanjuanbenito A, Ruz-Caracuel I, Rodríguez-Garrote M, Guerra C, Alfredo Carrato A, de Cárcer G, Sánchez L, Nombela-Arrieta C, Espinet E, Sanchez-Arevalo Lobo V J, Heeschen C, Bruno Sainz Jr B

The Peptidoglycan Recognition Protein 1 confers immune evasive properties on pancreatic cancer stem cells

Gut 2024

DOI

Objective Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options, particularly with immune checkpoint inhibitors. Highly chemoresistant ‘stem-like’ cells, known as cancer stem cells (CSCs), are implicated in PDAC aggressiveness. Thus, comprehending how this subset of cells evades the immune system is crucial for advancing novel therapies. Design We used the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre) and primary tumour cell lines to investigate putative CSC populations. Transcriptomic analyses were conducted to pinpoint new genes involved in immune evasion. Overexpressing and knockout cell lines were established with lentiviral vectors. Subsequent in vitro coculture assays, in vivo mouse and zebrafish tumorigenesis studies, and in silico database approaches were performed. Results Using the KPC mouse model, we functionally confirmed a population of cells marked by EpCAM, Sca-1 and CD133 as authentic CSCs and investigated their transcriptional profile. Immune evasion signatures/genes, notably the gene peptidoglycan recognition protein 1 (PGLYRP1), were significantly overexpressed in these CSCs. Modulating PGLYRP1 impacted CSC immune evasion, affecting their resistance to macrophage-mediated and T-cell-mediated killing and their tumourigenesis in immunocompetent mice. Mechanistically, tumour necrosis factor alpha (TNFα)-regulated PGLYRP1 expression interferes with the immune tumour microenvironment (TME) landscape, promoting myeloid cell-derived immunosuppression and activated T-cell death. Importantly, these findings were not only replicated in human models, but clinically, secreted PGLYRP1 levels were significantly elevated in patients with PDAC. Conclusions This study establishes PGLYRP1 as a novel CSC-associated marker crucial for immune evasion, particularly against macrophage phagocytosis and T-cell killing, presenting it as a promising target for PDAC immunotherapy.

Yıldız A, Răileanu C, Beissert T

Trans-Amplifying RNA: A Journey from Alphavirus Research to Future Vaccines

Viruses 2024

DOI

Vega-Sendino M, Lüttmann F, T Olbrich T, Yanpu Chen Y, Kuenne C, Stein P, Tillo D, Carey G, Zhong J, Savy V, Radonova L, Lu T, Saykali B, Kim K, Domingo C, Schüler L, Günther S, Bentsen M, Bosnakovski D, Schöler H, Kyba M, Maity T, Jenkins L, Looso M, Williams C, Kim J, Ruiz S

The homeobox transcription factor DUXBL controls exit from totipotency

Nat Genet. 2024

DOI

Beck J, Diken M, Suchan M, Streuber M, Diken E, Kolb L, Allnoch L, Vascotto F, Peters D, Beißert T, Akilli-Öztürk Ö, Türeci Ö, Kreiter- S, Vormehr M, Sahin U

Long-lasting mRNA-encoded interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers

Cancer Cell 2024

DOI

Kespohl M, Goetzke CC, Althof N, Bredow C, Kelm N, Pinkert S, Bukur T, Bukur V, Grunz K, Kaur D, Heuser A, Mülleder M, Sauter M, Klingel K, Weiler H, Berndt N, Gaida MM, Ruf W, Beling A

TF-FVIIa PAR2-β-Arrestin in Mouse Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection

Arterioscler Thromb Vasc Biol. 2024

DOI

Background: Accumulating evidence implicates the activation of G-protein-coupled PARs (protease-activated receptors) by coagulation proteases in the regulation of innate immune responses. Methods: Using mouse models with genetic alterations of the PAR2 signaling platform, we have explored contributions of PAR2 signaling to infection with coxsackievirus B3, a single-stranded RNA virus provoking multiorgan tissue damage, including the heart. Results: We show that PAR2 activation sustains correlates of severe morbidity-hemodynamic compromise, aggravated hypothermia, and hypoglycemia-despite intact control of the virus. Following acute viral liver injury, canonical PAR2 signaling impairs the restoration process associated with exaggerated type I IFN (interferon) signatures in response to viral RNA recognition. Metabolic profiling in combination with proteomics of liver tissue shows PAR2-dependent reprogramming of liver metabolism, increased lipid droplet storage, and gluconeogenesis. PAR2-sustained hypodynamic compromise, reprograming of liver metabolism, as well as imbalanced IFN responses are prevented in β-arrestin coupling-deficient PAR2 C-terminal phosphorylation mutant mice. Thus, wiring between upstream proteases and immune-metabolic responses results from biased PAR2 signaling mediated by intracellular recruitment of β-arrestin. Importantly, blockade of the TF (tissue factor)-FVIIa (coagulation factor VIIa) complex capable of PAR2 proteolysis with the NAPc2 (nematode anticoagulant protein c2) mitigated virus-triggered pathology, recapitulating effects seen in protease cleavage-resistant PAR2 mice. Conclusions: These data provide insights into a TF-FVIIa signaling axis through PAR2-β-arrestin coupling that is a regulator of inflammation-triggered tissue repair and hemodynamic compromise in coxsackievirus B3 infection and can potentially be targeted with selective coagulation inhibitors.

Park J, Kim Ju, Shin B, Schöler H R, Kim Jo, Kim K-P

Inducing Pluripotency in Somatic Cells: Historical Perspective and Recent Advances

Int J Stem Cells 2024

DOI

Göbel S, Braun AS, Hahad O, von Henning U, Brandt M, Keller K, Gaida MM, Gori T, Schultheiss HP, Escher F, Münzel T, Wenzel P.

Etiologies and predictors of mortality in an all-comer population of patients with non-ischemic heart failure

Clin Res Cardiol. 2024

DOI

Salomon N, Helm A, Selmi A, Fournier C, Diken M, Schrörs B, Scholz M, Kreiter S, Durante M, Vascotto F

Carbon ion and photon radiotherapy show enhanced anti-tumoral therapeutic efficacy with neoantigen RNA-LPX vaccines in preclinical colon carcinoma models

International Journal of Radiation Oncology, Biology, Physics (2023)

DOI

Schleussner N, Cauchy P, Franke V, Giefing M, Fornes O, Vankadari N, Assi SA, Costanza M, Weniger MA, Akalin A, Anagnostopoulos I, Bukur T, Casarotto MG, Damm F, Daumke O, Edginton-White B, Gebhardt JCM, Grau M, Grunwald S, Hansmann ML, Hartmann S, Huber L, Kärgel E, Lusatis S, Noerenberg D, Obier N, Pannicke U, Fischer A, Reisser A, Rosenwald A, Schwarz K, Sundararaj S, Weilemann A, Winkler W, Xu W, Lenz G, Rajewsky K, Wasserman WW, Cockerill PN, Scheidereit C, Siebert R, Küppers R, Grosschedl R, Janz M, Bonifer C, Mathas S.

Transcriptional reprogramming by mutated IRF4 in lymphoma

Nat Commun. 2023 Nov 7;14(1):6947

DOI

Bähr-Mahmud H, Ellinghaus U, Stadler CR, Fischer L, Lindemann C, Chaturvedi A, Diekmann J, Wöll S, Biermann I, Hebich B, Scharf C, Siefke M, Roth AS, Rao M, Brettschneider K, Ewen EM, Şahin U, Türeci Ö.

Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody

Oncoimmunology . 2023 Oct 16;12(1):2255041

DOI

Kohlruss M, Chakraborty S, Hapfelmeier A, Jesinghaus M, Slotta-Huspenina J, Novotny A, Sisic L, Gaida MM, Ott K, Weichert W, Pfarr N, Keller G.

Low microsatellite instability: A distinct instability type in gastric cancer?

J Cancer Res Clin Oncol . 2023 Oct 11. doi: 10.1007/s00432-023-05430-6

DOI

Lang F, Sorn P, Schrörs B, Weber D, Kramer S, Sahin U, Löwer L

Multiple instance learning to predict immune checkpoint blockade efficacy using neoantigen candidates

iScience, Volume 26, Issue 11, 17 November 2023, 108014

DOI

Dallmann J, Freitag J, Jung C, Khinvasara K, Merz L, Peters D, Schork M, Beck JD

CIMT 2023: report on the 20th Annual Meeting of the Association for Cancer Immunotherapy

Immunooncol Technol . 2023 Sep 12:20:100397

DOI

Bosnakovski D, Toso EA, Ener ET, Gearhart MD, Yin L, Lüttmann FF, Magli A, Shi K, Kim J, Aihara H, Kyba M

Antagonism among DUX family members evolved from an ancestral toxic single homeodomain protein

iScience. 2023 Sep 2;26(10):107823

DOI

Hefermehl AK, Hensen SM, Versantvoort C, Rothermel A, Sahin U

Automated glycan-bead coupling for high throughput, highly reproducible anti-glycan antibody analysis

SLAS Technology 2023

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Wilhelmy C, Keil IS, Uebbing L, Schroer MA, Franke D, Nawroth T, Barz M, Sahin U, Haas H, Diken M, Langguth P

Polysarcosine-Functionalized mRNA Lipid Nanoparticles Tailored for Immunotherapy

Pharmaceutics 2023, 15(8), 2068

DOI

Lipid nanoparticles (LNPs) have gained great attention as carriers for mRNA-based therapeutics, finding applications in various indications, extending beyond their recent use in vaccines for infectious diseases. However, many aspects of LNP structure and their effects on efficacy are not well characterized. To further exploit the potential of mRNA therapeutics, better control of therelationship between LNP formulation composition with internal structure and transfection efficiency in vitro is necessary. We compared two well-established ionizable lipids, namely DODMA and MC3, in combination with two helper lipids, DOPE and DOPC, and two polymer-grafted lipids, either with polysarcosine (pSar) or polyethylene glycol (PEG). In addition to standard physicochemical characterization (size, zeta potential, RNA accessibility), small-angle X-ray scattering (SAXS) was used to analyze the structure of the LNPs. To assess biological activity, we performed transfection and cell-binding assays in human peripheral blood mononuclear cells (hPBMCs) using Thy1.1 reporter mRNA and Cy5-labeled mRNA, respectively. With the SAXS measurements, we were able to clearly reveal the effects of substituting the ionizable and helper lipid on the internal structure of the LNPs. In contrast, pSar as stealth moieties affected the LNPs in a different manner, by changing the surface morphology towards higher roughness. pSar LNPs were generally more active, where the highest transfection efficiency was achieved with the LNP formulation composition of MC3/DOPE/pSar. Our study highlights the utility of pSar for improved mRNA LNP products and the importance of pSar as a novel stealth moiety enhancing efficiency in future LNP formulation development. SAXS can provide valuable information for the rational development of such novel formulations by elucidating structural features in different LNP compositions.

Kriegsmann M, Kriegsmann K, Steinbuss G, Zgorzelski C, Albrecht T, Heinrich S, Farkas S, Roth W, Dang H, Hausen A, Gaida M.

Implementation of deep learning in liver pathology optimizes diagnosis of benign lesions and adenocarcinoma metastasis

Clin Transl Med. 2023; 13:e1299

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Peri A, Salomon N , Wolf, Y, Kreiter S, Diken M, Samuels Y

The landscape of T cell antigens for cancer immunotherapy

Nat Cancer . 2023 Jul 6.

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Bukur T, Riesgo-Ferreiro, Sorn P, Gudimella R, Hausmann J, Roesler T, Loewer M, Schroers B, and Sahin U

CoVigator—A Knowledge Base for Navigating SARS-CoV-2 Genomic Variants

Viruses 2023, 15(6), 1391

DOI

Yousuf S, Qiu M, Voithenberg LVv, Hulkkonen J, Macinkovic I, Schulz AR, Hartmann D, Mueller F, Mijatovic M, Ibberson D, AlHalabi KT, Hetzer J, Anders S, Bruene B, Mei HE, Imbusch CD, Brors B, Heikenwaelder M, Gaida MM, Buechler MW, Weigert A, Hackert T, Roth S

Spatially resolved multi-omics single-cell analyses inform mechanisms of immune-dysfunction in pancreatic cancer

Gastroenterology 2023

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Hiltner T, Kohlruss M, Herz A-L, Lorenzen S, Novotny A, Hapfelmeier A, Jesinghaus M, Slotta Huspenina J, Sisic L, Gaida MM, Weichert W, Ott K, Keller G

Microsatellite instability and sex-specific differences of survival in gastric cancer after neoadjuvant chemotherapy without and with taxane: An observational study in real world patients

J Cancer Res Clin Oncol 2023

DOI

Saerchen V, Reindl L, Wiedemann S, Shanmugalingam S, Bukur T, Becker J, Suchan M, Ullrich E, Vogler M.

Characterization of BV6-Induced Sensitization to the NK Cell Killing of Pediatric Rhabdomyosarcoma Spheroids

Cells 2023, 12(6), 906

DOI

Schroers B, Hos B, Yildiz I, Loewer M, Lang F, Holtstraeter C, Becker J, Vormehr M, Sahin U, Ossendorp F, Diken M

MC38 colorectal tumor cell lines from two different sources display substantial differences in transcriptome, mutanome and neoantigen expression

Front. Immunol., 08 March 2023

DOI

Jeong YJ, Knutsdottir H, Shojaeian F, Lerner M, Wissler M, Henriet E, Ng T, Datta S, Navarro-Serer B, Chianchiano P, Kinny-Köster B, Zimmerman J, Stein-O'Brien G, Gaida M, Eshleman J, Lin M, Fertig E, Ewald A, Bader J, Wood LD

Morphology-guided transcriptomic analysis of human pancreatic cancer organoids reveals microenvironmental signals that enhance invasion

J Clin Invest . 2023 Mar 7

DOI PMID

Picard FSR, Lutz V, Brichkina A, Neuhaus F, Ruckenbrod T, Hupfer A, Raifer H, Klein M, Bopp T, Pfefferle PI, Savai R, Prinz I, Waisman A, Moos S, Chang HD, Heinrich S, Bartsch DK, Buchholz M, Singh S, Tu M, Klein L, Bauer C, Liefke R, Burchert A, Chung HR, Mayer P, Gress TM, Lauth M, Gaida M, Huber M.

IL-17A-producing CD8+ T cells promote PDAC via induction of inflammatory cancer-associated fibroblasts

Gut. 2023 Feb 9:gutjnl-2022-327855.

DOI

Objective: Pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant desmoplastic stroma composed of cancer-associated fibroblasts (CAF) and interspersed immune cells. A non-canonical CD8+ T-cell subpopulation producing IL-17A (Tc17) promotes autoimmunity and has been identified in tumours. Here, we evaluated the Tc17 role in PDAC. Design: Infiltration of Tc17 cells in PDAC tissue was correlated with patient overall survival and tumour stage. Wild-type (WT) or Il17ra-/- quiescent pancreatic stellate cells (qPSC) were exposed to conditional media obtained from Tc17 cells (Tc17-CM); moreover, co-culture of Tc17-CM-induced inflammatory (i)CAF (Tc17-iCAF) with tumour cells was performed. IL-17A/F-, IL-17RA-, RAG1-deficient and Foxn1nu/nu mice were used to study the Tc17 role in subcutaneous and orthotopic PDAC mouse models. Results: Increased abundance of Tc17 cells highly correlated with reduced survival and advanced tumour stage in PDAC. Tc17-CM induced iCAF differentiation as assessed by the expression of iCAF-associated genes via synergism of IL-17A and TNF. Accordingly, IL-17RA controlled the responsiveness of qPSC to Tc17-CM. Pancreatic tumour cells co-cultured with Tc17-iCAF displayed enhanced proliferation and increased expression of genes implicated in proliferation, metabolism and protection from apoptosis. Tc17-iCAF accelerated growth of mouse and human tumours in Rag1-/- and Foxn1nu/nu mice, respectively. Finally, Il17ra-expressed by fibroblasts was required for Tc17-driven tumour growth in vivo. Conclusions: We identified Tc17 as a novel protumourigenic CD8+ T-cell subtype in PDAC, which accelerated tumour growth via IL-17RA-dependent stroma modification. We described a crosstalk between three cell types, Tc17, fibroblasts and tumour cells, promoting PDAC progression, which resulted in poor prognosis for patients.

Perkovic M, Gawletta S, Hempel T, Brill S, Nett E, Sahin U, Beissert T.

A trans-amplifying RNA simplified to essential elements is highly replicative and robustly immunogenic in mice

Mol Ther. 2023 Jan 23:S1525-0016(23)00019-9

DOI

Stern L, Boehme LF, Goetz MR, Nitschke C, Giannou A, Zhang T, Gungor C, Reeh M, Izbicki JR, Fliegert R, Hausen A, Giese N, Hackert T, Niv MY, Heinrich S, Gaida MM, and Ghadban T.

Potential role of the bitter taste receptor T2R14 in the prolonged survival and enhanced chemoresponsiveness induced by apigenin.

Int J Oncol 62(1):6

DOI

Yan B, Liu L, Zhao L, Hinz U, Luo Y, An X, Gladkich J, de la Torre C, Huang Z, Schrapel D, Gross W, Fortunato F, Schäfer M, Gaida MM, Herr I.

Tumor and stroma COL8A1 secretion induces autocrine and paracrine progression signaling in pancreatic ductal adenocarcinoma.

Matrix Biol. 2022 Nov 11:S0945-053X(22)00134-2.

DOI

Krähling V, Erbar S, Kupke A, Nogueira SS, Walzer KC, Berger H, Dietzel E, Halwe S, Rohde C, Sauerhering L, Aragão-Santiago L, Moreno Herrero J, Witzel S, Haas H, Becker S, Sahin U.

Self-amplifying RNA vaccine protects mice against lethal Ebola virus infection.

Mol Ther. 2022 Oct 27:S1525-0016(22)00623-2.

DOI PMID

Wang J, Weiss T, Neidert MC, Toussaint NC, Naghavian R, Moreno Sellés C, Foege M, Tomas Ojer P, Medici G, Jelcic I, Schulz D, Rushing E, Dettwiler S, Schrörs B, Shin JH, McKay R, Wu CJ, Lutterotti A, Sospedra M, Moch H, Greiner EF, Bodenmiller B, Regli L, Weller M, Roth P, Martin R.

Vaccination with designed neopeptides induces intratumoral, cross-reactive CD4+ T cell responses in glioblastoma.

Clin Cancer Res. 2022 Oct 13:CCR-22-1741.

DOI PMID

Schmidt C, Hastert FD, Gerbeth J, Beissert T, Sahin U, Perkovic M, Schnierle BS.

A Bivalent Trans-Amplifying RNA Vaccine Candidate Induces Potent Chikungunya and Ross River Virus Specific Immune Responses.

Vaccines (Basel). 2022 Aug 23;10(9):1374.

DOI PMID

Birtel M, Voss RH, Reinhard K, Rengstl B, Ouchan Y, Michel K, Hayduk N, Tillmann B, Becker R, Suchan M, Theobald M, Oehm P, Türeci Ö, Sahin U

A TCR-like CAR Promotes Sensitive Antigen Recognition and Controlled T-cell Expansion Upon mRNA Vaccination

Cancer Res. Comm. 2022. 2 (8): 827–841

DOI

Sahu SK, Agirre E, Inayatullah M, Mahesh A, Tiwari N, Lavin DP, Singh A, Strand S, Diken M, Luco RF, Belmonte JCI, Tiwari VK

A complex epigenome-splicing crosstalk governs epithelial-to-mesenchymal transition in metastasis and brain development

Nat. Cell Biol. 2022 Aug; 24(8):1265-1277

DOI PMID

Fonteneau G, Redding A, Hoag-Lee H, Sim ES, Heinrich S, Gaida MM, and Grabocka E

Stress Granules determine the Development of Obesity-associated Pancreatic Cancer.

Cancer Discov. 2022 Aug 5;12(8):1984-200

DOI

Brindl N, Boekhoff H, Bauer AS, Gaida MM, Dang HT, Kaiser J, Hoheisel JD, Felix K

Use of Autoreactive Antibodies in Blood of Patients with Pancreatic Intraductal Papillary Mucinous Neoplasms (IPMN) for Grade Distinction and Detection of Malignancy

Cancers 2022, 14, 3562

DOI PMID

Muik A, Adams 3rd HC, Gieseke F, Altintas I, Schoedel KB, Blum JM, Sänger B, Burm SM, Stanganello E, Verzijl D, Spires VM, Vascotto F, Toker A, Quinkhardt J, Fereshteh M, Diken M, Satijn DPE, Kreiter S, Ahmadi T, Breij ECW, Türeci Ö, Sasser K, Sahin U, Jure-Kunkel M.

DuoBody-CD40x4-1BB induces dendritic-cell maturation and enhances T-cell activation through conditional CD40 and 4-1BB agonist activity.

Journal for Immunotherapy of Cancer. 2022 Jun;10(6):e004322.

DOI

Schmidt C, Haefner E, Gerbeth J, Beissert T, Sahin U, Perkovic M, Schnierle BS.

A taRNA vaccine candidate induces a specific immune response that protects mice against Chikungunya virus infections.

Nucleic Acids. 2022 Jun;28:743-754.

DOI

Muik A, Garralda E, Altintas I, Gieseke F, Geva R, Ben-Ami E, Maurice-Dror C, Calvo E, LoRusso PM, Alonso G, Rodriguez-Ruiz ME, Schoedel KB, Blum JM, Sänger B, Salcedo TW, Burm SM, Stanganello E, Verzijl D, Vascotto F, Sette A, Quinkhardt J, Plantinga TS, Toker A, van den Brink EN, Fereshteh M, Diken M, Satijn D, Kreiter S, Breij ECW, Bajaj G, Lagkadinou E, Sasser K, Türeci Ö, Forssmann U, Ahmadi T, Şahin U, Jure-Kunkel M, Melero I.

Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors.

Cancer Discov. 2022 May 2;12(5):1248-1265.

DOI PMID

Lang F, Schrörs B, Löwer M, Türeci Ö, Sahin U.

Identification of neoantigens for individualized therapeutic cancer vaccines.

Nat Rev Drug Discov. 2022 Apr;21(4):261-282.

DOI PMID

Voss M, Pinkert S, Kespohl M, Gimber N, Klingel K, Schmoranzer J, Laue M, Gaida M, Kloetzel PM, and Beling A

A Conserved Cysteine Residue in Coxsackievirus B3 Protein 3A with Implication for Elevated Virulence.

Viruses. 2022 Apr 7;14(4):769

DOI

Weber D, Ibn-Salem J, Sorn P, Suchan M, Holtsträter C, Lahrmann U, Vogler I, Schmoldt K, Lang F, Schrörs B, Löwer M, Sahin U.

Accurate detection of tumor-specific gene fusions reveals strongly immunogenic personal neo-antigens.

Nat Biotechnol. 2022 Apr 4.

DOI PMID

Kaps L, Huppertsberg A, Choteschovsky N, Klefenz A, Durak F, Schrörs B, Diken M, Eichler E, Rosigkeit S, Schmitt S, Leps C, Schulze A, Foerster F, Bockamp E, De Geest B, Koynov K, Räder H, Stefan Tenzer S, Marini F, Schuppan D, Nuhn, L.

pH-degradable, bisphosphonate-loaded nanogels attenuate liver fibrosis by repolarization of M2-type macrophages.

Proc Natl Acad Sci U S A. 2022 Mar 22;119(12):e2122310119.

DOI PMID

Schäfer MEA, Keller F, Schumacher J, Haas H, Vascotto F, Sahin U, Hafner M, Rudolf R.

3D Melanoma Cocultures as Improved Models for Nanoparticle-Mediated Delivery of RNA to Tumors.

Cells. 2022 Mar 17;11(6):1026.

DOI PMID

Muik A, Altintas I, Gieseke F, Schoedel KB, Burm SM, Toker A, Salcedo TW, Verzijl D, Eisel D, Grunwitz C, Kranz LM, Vormehr M, Satijn DPE, Diken M, Kreiter S, Sasser K, Ahmadi T, Türeci Ö, Breij ECW, Jure-Kunkel M, Sahin U.

An Fc-inert PD-L1×4-1BB bispecific antibody mediates potent anti-tumor immunity in mice by combining checkpoint inhibition and conditional 4-1BB co-stimulation.

Oncoimmunology. 2022 Feb 16;11(1):2030135.

DOI PMID

Riesgo-Ferreiro P, Gudimella R, Bukur T, Patrick Sorn P, Rösler T, Schrörs B, Löwer M.

In silico analysis of predicted differential MHC binding and CD8+ T-cell immune escape of SARS-CoV-2 B.1.1.529 variant mutant epitopes.

Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv.

DOI

Kilian M, Friedrich M, Sanghvi K, Green E, Pusch S, Kawauchi D, Löwer M, Sonner JK, Krämer C, Zaman J, Jung S, Breckwoldt MO, Willimsky G, Eichmüller SB, von Deimling A, Wick W, Sahm F, Platten M, Bunse L.

T-cell Receptor Therapy Targeting Mutant Capicua Transcriptional Repressor in Experimental Gliomas.

Clin Cancer Res. 2022 Jan 15;28(2):378-389.

DOI PMID

Salomon N, Selmi A, Grunwitz C, Kong A, Stanganello E, Neumaier J, Petschenka J, Diken M, Kreiter S, Türeci Ö, Sahin U, Vascotto F. (2021)

Local radiotherapy and E7 RNA-LPX vaccination show enhanced therapeutic efficacy in preclinical models of HPV16+ cancer.

Cancer Immunol Immunother. 2021 Dec 31.

DOI PMID

Alishah K, Birtel M, Masoumi E, Jafarzadeh L, Mirzaee HR, Hadjati J, Voss RH, Diken M, Asad S. (2021)

CRISPR/Cas9-mediated TGFβRII disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells in vitro.

J Transl Med. 2021 Nov 27;19(1):482.

DOI PMID

Weiden J, Schluck M, Ioannidis M, van Dinther EAW, Rezaeeyazdi M, Omar F, Steuten J, Voerman D, Tel J, Diken M, Bencherif SA, Figdor CG, Verdoes M. (2021)

Robust Antigen-Specific T Cell Activation within Injectable 3D Synthetic Nanovaccine Depots.

ACS Biomater. Sci. Eng. https://pubs.acs.org/doi/10.1021/acsbiomaterials.0c01648.

DOI

Tadmor AD, Phillips R. (2021)

MCRL: using a reference library to compress a metagenome into a nonredundant list of sequences, considering viruses as a case study.

Bioinformatics, btab703.

DOI

Schrörs B, Riesgo-Ferreiro P, Sorn P, Gudimella R, Bukur T, Rösler T, Löwer M, Sahin U. (2021)

Large-scale analysis of SARS-CoV-2 spike-glycoprotein mutants demonstrates the need for continuous screening of virus isolates.

PLoS One. 16(9):e0249254.

DOI

Formes H, Bernardes JP, Mann A, Bayer F, Pontarollo G, Kiouptsi K, Schäfer K, Attig S, Nikolova T, Hofmann TG, Schattenberg JM, Todorov H, Gerber S, Rosenstiel P, Bopp T, Sommer F, Reinhardt C. (2021)

The gut microbiota instructs the hepatic endothelial cell transcriptome.

iScience. 24(10):103092.

DOI

Hotz C, Wagenaar TR, Gieseke F, Bangari DS, Callahan M, Cao H, Diekmann J, Diken M, Grunwitz C, Hebert A, Hsu K, Bernardo M, Karikó K, Kreiter S, Kuhn AN, Levit M, Malkova N, Masciari S, Pollard J, Qu H, Ryan S, Selmi A, Schlereth J, Singh K, Sun F, Tillmann B, Tolstykh T, Weber W, Wicke L, Witzel S, Yu Q, Zhang YA, Zheng G, Lager J, Nabel GJ, Sahin U, Wiederschain D. (2021)

Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models.

Sci Transl Med. 13(610):eabc7804.

DOI

Kappel C, Seidl C, Medina-Montano C, Schinnerer M, Alberg I, Leps C, Sohl J, Hartmann AK, Fichter M, Kuske M, Schunke J, Kuhn G, Tubbe I, Paßlick D, Hobernik D, Bent R, Haas K, Montermann E, Walzer K, Diken M, Schmidt M, Zentel R, Nuhn L, Schild H, Tenzer S, Mailänder V, Barz M, Bros M, Grabbe S. (2021)

Density of Conjugated Antibody Determines the Extent of Fc Receptor Dependent Capture of Nanoparticles by Liver Sinusoidal Endothelial Cells.

ACS Nano 15(9):15191-15209.

DOI

Bresadola L, Weber D, Ritzel C, Löwer M, Bukur V, Akilli-Öztürk Ö, Becker J, Mehanna H, Schrörs B, Vascotto F, Sahin U, Kong A. (2021)

Comprehensive Genomic and Transcriptomic Analysis of Three Synchronous Primary Tumours and a Recurrence from a Head and Neck Cancer Patient.

Int J Mol Sci. 2021 Jul 15;22(14):7583.

DOI

Lang F, Ferreiro PR, Löwer M, Sahin U, Schrörs B. (2021)

NeoFox: annotating neoantigen candidates with neoantigen features

Bioinformatics. 2021 May 10:btab344.

DOI

Beck JD, Reidenbach D, Salomon N, Sahin U, Türeci Ö, Vormehr M, Kranz LM. (2021)

mRNA therapeutics in cancer immunotherapy.

Mol Cancer. 20(1):69. doi: 10.1186/s12943-021-01348-0.

DOI

Dölen Y, Gileadi U, Chen JL, Valente M, Creemers JHA, Van Dinther EAW, van Riessen NK, Jäger E, Hruby M, Cerundolo V, Diken M, Figdor CG, de Vries IJM. (2021)

PLGA Nanoparticles Co-encapsulating NY-ESO-1 Peptides and IMM60 Induce Robust CD8 and CD4 T Cell and B Cell Responses.

Front Immunol. 12:641703.

DOI

Miederer M, Pektor S, Miederer I , Bausbacher N, Keil IS, Hefesha H, Haas H, Sahin U, Diken M. (2021)

Iodine-124 PET quantification of organ-specific delivery and expression of NIS-encoding RNA.

EJNMMI Res 11, 14.

DOI PMID

Aravamudhan S, Türk C, Bock T, Keufgens L, Nolte H, Lang F, Krishnan RK, König T, Hammerschmidt P, Schindler N, Brodesser S, Rozsivalova DH, Rugarli E, Trifunovic A, Brüning J, Langer T, Braun T, Krüger M. (2021)

Phosphoproteomics of the developing heart identifies PERM1 – An outer mitochondrial membrane protein.

J Mol Cell Cardiol. 154:41-59.

DOI

Vogel AB, Kanevsky I, Che Y, et al. (2021)

Immunogenic BNT162b vaccines protect rhesus macaques from SARS-CoV-2.

Nature. https://doi.org/10.1038/s41586-021-03275-y.

DOI PMID

Costa B, Fletcher MNC, Boskovic P, Ivanova EL, Eisemann T, Lohr S, Bunse L, Löwer M, Burchard S, Korshunov A, Coltella N, Cusimano M, Naldini L, Liu HK, Platten M, Radlwimmer B, Angel P, Peterziel H. (2021)

A Set of Cell Lines Derived from a Genetic Murine Glioblastoma Model Recapitulates Molecular and Morphological Characteristics of Human Tumors.

Cancers (Basel).13(2):230.

DOI

Krienke C, Kolb L, Diken E, Streuber M, Kirchhoff S, Bukur T, Akilli-Öztürk Ö, Kranz LM, Berger H, Petschenka J, Diken M, Kreiter S, Yogev N, Waisman A, Karikó K, Türeci Ö, Sahin U. (2021)

A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis.

Science. 371(6525):145-153.

DOI PMID

Christina Krienke (2021)

Novel RNA-Based therapy for treatment of autoimmune diseases.

Science.

DOI

Sethi R, Becker J, de Graaf J, Löwer M, Suchan M, Sahin U, Weber D

Integrative analysis of structural variations using short-reads and linked-reads yields highly specific and sensitive predictions

PLoS Comput Biol 16(11): e1008397

DOI

Sahin U, Oehm P, Derhovanessian E, Jabulowsky RA, Vormehr M, Gold M, Maurus D, Schwarck-Kokarakis D, Kuhn AN, Omokoko T, Kranz LM, Diken M, Kreiter S, Haas H, Attig S, Rae R, Cuk K, Kemmer-Brück A, Breitkreuz A, Tolliver C, Caspar J, Quinkhardt J, Hebich L, Stein M, Hohberger A, Vogler I, Liebig I, Renken S, Sikorski J, Leierer M, Müller V, Mitzel-Rink H, Miederer M, Huber C, Grabbe S, Utikal J, Pinter A, Kaufmann R, Hassel JC, Loquai C, Türeci Ö. (2020)

An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma.

Nature.

DOI

Schrörs B, Boegel S, Albrecht C, Bukur T, Bukur V, Holtsträter C, Ritzel C, Manninen K, Tadmor AD, Vormehr M, Sahin U, Löwer M. (2020)

Multi-Omics Characterization of the 4T1 Murine Mammary Gland Tumor Model.

Frontiers in Oncology.

DOI

Background: Tumor models are critical for our understanding of cancer and the development of cancer therapeutics. The 4T1 murine mammary cancer cell line is one of the most widely used breast cancer models. Here, we present an integrated map of the genome, transcriptome, and immunome of 4T1.Results: We found Trp53 (Tp53) and Pik3g to be mutated. Other frequently mutated genes in breast cancer, including Brca1 and Brca2, are not mutated. For cancer related genes, Nav3, Cenpf, Muc5Ac, Mpp7, Gas1, MageD2, Dusp1, Ros, Polr2a, Rragd, Ros1, and Hoxa9 are mutated. Markers for cell proliferation like Top2a, Birc5, and Mki67 are highly expressed, so are markers for metastasis like Msln, Ect2, and Plk1, which are known to be overexpressed in triple-negative breast cancer (TNBC). TNBC markers are, compared to a mammary gland control sample, lower (Esr1), comparably low (Erbb2), or not expressed at all (Pgr). We also found testis cancer antigen Pbk as well as colon/gastrointestinal cancer antigens Gpa33 and Epcam to be highly expressed. Major histocompatibility complex (MHC) class I is expressed, while MHC class II is not. We identified 505 single nucleotide variations (SNVs) and 20 insertions and deletions (indels). Neoantigens derived from 22 SNVs and one deletion elicited CD8+ or CD4+ T cell responses in IFNγ-ELISpot assays. Twelve high-confidence fusion genes were observed. We did not observe significant downregulation of mismatch repair (MMR) genes or SNVs/indels impairing their function, providing evidence for 6-thioguanine resistance. Effects of the integration of the murine mammary tumor virus were observed at the genome and transcriptome level.Conclusions: 4T1 cells share substantial molecular features with human TNBC. As 4T1 is a common model for metastatic tumors, our data supports the rational design of mode-of-action studies for pre-clinical evaluation of targeted immunotherapies.

Nadja Salomon (2020)

A liposomal RNA vaccine augments the antitumor activity of local radiotherapy in mice

Taylor & Francis Online

DOI

Salomon N, Vascotto F, Selmi A, Vormehr M, Quinkhardt J, Bukur T, Schrörs B, Löwer M, Diken M, Türeci Ö, Sahin U, Kreiter S. (2020)

A liposomal RNA vaccine inducing neoantigen-specific CD4+ T cells augments the antitumor activity of local radiotherapy in mice.

Oncoimmunology. 9:1771925.

DOI

Barea Roldán D, Grimmler M, Hartmann C, Hubich-Rau S, Beiβert T, Paret C, Cagna G, Rohde C, Wöll S, Koslowski M, Türeci O, Sahin U. (2020)

PLAC1 is essential for FGF7/FGFRIIIb-induced Akt-mediated cancer cell proliferation.

Oncotarget. 11:1862-1875.

DOI PMID

Schöpf B, Weissensteiner H, Schäfer G, Fazzini F, Charoentong P, Naschberger A, Rupp B, Fendt L, Bukur V, Giese I, Sorn P, Sant’Anna-Silva AC, Iglesias-Gonzalez J, Sahin U, Kronenberg F, Gnaiger E, Klocker H. (2020)

OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation.

Nat. Comm. 11(1):1487.

DOI PMID

Holtsträter C, Schrörs B, Bukur T, Löwer M. (2020)

Bioinformatics for Cancer Immunotherapy.

In: Methods Mol Biol. 2120:1-9. Springer.

DOI PMID

Vormehr M, Diken M, Türeci Ö, Sahin U, Kreiter S. (2019)

Personalized Neo-Epitope Vaccines for Cancer Treatment.

In: Theobald M. (eds) Current Immunotherapeutic Strategies in Cancer. Recent Results in Cancer Research. 214:153-167. Springer.

DOI PMID

Reinhard K, Rengstl B, Oehm P, Michel K, Billmeier A, Hayduk N, Klein O, Kuna K, Ouchan Y, Wöll S, Christ E, Weber D, Suchan M, Bukur T, Birtel M, Jahndel V, Mroz K, Hobohm K, Kranz L, Diken M, Kühlcke K, Türeci Ö, Sahin U. (2020)

An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors.

Science. 367:446-453.

DOI PMID

Beissert T, Perkovic M, Vogel A, Erbar S, Walzer KC, Hempel T, Brill S, Haefner E, Becker R, Türeci Ö, Sahin U. (2019)

A trans-amplifying RNA vaccine strategy for induction of potent protective immunity.

Mol Ther. pii: S1525-0016(19)30412-5.

DOI PMID

Sorn P, Holtsträter C, Löwer M, Sahin U, Weber D. (2019)

ArtiFuse – Computational validation of fusion gene detection tools without relying on simulated reads.

Bioinformatics. pii: btz613.

DOI PMID

Grunwitz C, Salomon N, Vascotto F, Selmi A, Bukur T, Diken M, Kreiter S, Türeci Ö, Sahin U. (2019)

HPV16 RNA-LPX vaccine mediates complete regression of aggressively growing HPV-positive mouse tumors and establishes protective T cell memory.

Oncoimmunology. 8:e1629259.

DOI PMID

Vascotto F, Petschenka J, Walzer KC, Vormehr M, Brkic M, Strobl S, Rösemann R, Diken M, Kreiter S, Türeci Ö, Sahin U. (2019)

Intravenous delivery of the toll-like receptor 7 agonist SC1 confers tumor control by inducing a CD8+ T cell response.

Oncoimmunology. 8:e1601480.

DOI PMID

Orlandini von Niessen AG, Poleganov MA, Rechner C, Plaschke A, Kranz LM, Fesser S, Diken M, Löwer M, Vallazza B, Beissert T, Bukur V, Kuhn AN, Türeci Ö, Sahin U. (2019)

Improving mRNA-Based Therapeutic Gene Delivery by Expression-Augmenting 3′ UTRs Identified by Cellular Library Screening.

Mol Ther. 27:824-836.

DOI PMID

Vormehr M, Türeci Ö, Sahin U. (2019)

Harnessing Tumor Mutations for Truly Individualized Cancer Vaccines.

Annu Rev Med. 70:395-407.

DOI PMID

Vormehr M, Reinhard K, Blatnik R, Josef K, Beck JD, Salomon N, Suchan M, Selmi A, Vascotto F, Zerweck J, Wenschuh H, Diken M, Kreiter S, Türeci Ö, Riemer AB, Sahin U. (2018)

A non-functional neoepitope specific CD8+ T-cell response induced by tumor derived antigen exposure in vivo.

Oncoimmunology.

DOI PMID

Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanović S, Gouttefangeas C, Platten M, Tabatabai G, Dutoit V, van der Burg SH, Thor Straten P, Martínez-Ricarte F, Ponsati B, Okada H, Lassen U, Admon A, Ottensmeier CH, Ulges A, Kreiter S, von Deimling A, Skardelly M, Migliorini D, Kroep JR, Idorn M, Rodon J, Piró J, Poulsen HS, Shraibman B, McCann K, Mendrzyk R, Löwer M, Stieglbauer M, Britten CM, Capper D, Welters MJP, Sahuquillo J, Kiesel K, Derhovanessian E, Rusch E, Bunse L, Song C, Heesch S, Wagner C, Kemmer-Brück A, Ludwig J, Castle JC, Schoor O, Tadmor AD, Green E, Fritsche J, Meyer M, Pawlowski N, Dorner S, Hoffgaard F, Rössler B, Maurer D, Weinschenk T, Reinhardt C, Huber C, Rammensee HG, Singh-Jasuja H, Sahin U, Dietrich PY, Wick W. (2018)

Actively personalized vaccination trial for newly diagnosed glioblastoma.

Nature

DOI PMID

Fiore A, Ugel S, Sanctis FD, Sandri S, Fracasso G, Trovato R, Sartoris S, Solito S, Mandruzzato S, Vascotto F, Hippen KL, Mondanelli G, Grohmann U, Piro G, Carbone C, Melisi D, Lawlor RT, Scarpa A, Lamolinara A, Iezzi M, Fassan M, Bicciato S, Blazar BR, Sahin U, Murray PJ, Bronte V. (2018)

Induction of immunosuppressive functions and NF-kB by FLIP in monocytes.

Nat Commun. 9:5193

DOI PMID

Sun Q, Barz M, De Geest BG, Diken M, Hennink WE, Kiessling F, Lammers T, Shi Y. (2018)

Nanomedicine and macroscale materials in immuno-oncology.

Chem Soc Rev. 48(1):351-381

DOI PMID

Pastor F, Berraondo P, Etxeberria I, Frederick J, Sahin U, Gilboa E and Melero I. (2018)

An RNA toolbox for cancer immunotherapy.

Nat Rev. Drug Discov. 17(10):751-767

DOI PMID

Pektor S, Hilscher L, Walzer KC, Miederer I, Bausbacher N, Loquai C, Schreckenberger M, Sahin U, Diken M, Miederer M. (2018)

In vivo imaging of the immune response upon systemic RNA cancer vaccination by FDG-PET.

EJNMMI Res. 8(1):80

DOI PMID

BACKGROUND: [18F]Fluoro-2-deoxy-2-d-glucose positron emission tomography (FDG-PET) is commonly used in the clinic for diagnosis of cancer and for follow-up of therapy outcome. Additional to the well-established value in tumor imaging, it bears potential to depict immune processes in modern immunotherapies. T cells enhance their glucose consumption upon activation and are crucial effectors for the success of such novel therapies. In this study, we analyzed the T cell immunity in spleen after antigen-specific stimulation of T cells via highly innovative RNA-based vaccines using FDG-PET/MRI. For this purpose, we employed systemic administration of RNA-lipoplexes encoding the endogenous antigen of Moloney murine leukemia virus (gp70) which have been previously shown to induce potent innate as well as adaptive immune mechanisms for cancer immunotherapy. Feasibility of clinical imaging of increased splenic FDG uptake was demonstrated in a melanoma patient participating in a clinical phase 1 trial of a tetravalent RNA-lipoplex cancer vaccine.‍RESULTS: We observed exclusive increase of glucose uptake in spleen compared to other organs thanks to liposome-mediated RNA targeting to this immune-relevant organ. In vivo and ex vivo FDG uptake analysis in the spleen of vaccinated mice correlated well with antigen-specific T cell activation. Moreover, the use of an irrelevant (antigen non-specific) RNA also resulted in enhanced FDG uptake early after vaccination through the activation of several other splenic cell populations. The glucose uptake was also dependent on the dose of RNA administered in line with the activation and frequencies of proliferating antigen-specific T cells as well as the general activation pattern of splenic cell populations.CONCLUSIONS: Our preclinical results show rapid and transient vaccination-induced increase of FDG uptake within the spleen reflecting immune activation preceding T cell proliferation. FDG-PET/CT in patients is also capable to image this immune activation resulting in a new potential application of FDG-PET/CT to image immune processes in new immunological therapies.‍

Türeci Ö, Löwer M, Schrörs B, Lang M, Tadmor A, Sahin U. (2018)

Challenges towards the realization of individualized cancer vaccines.

Nat Biomed Eng. 19:747

DOI

Boegel S, Bukur T, Castle JC, Sahin U. (2018)

In Silico Typing of Classical and Non-classical HLA Alleles from Standard RNA-Seq Reads

Methods Mol Biol. 1802:177-191

DOI PMID

Bidmon N, Kind S, Welters MJP, Joseph-Pietras D, Laske K, Maurer D, Hadrup SR, Schreibelt G, Rae R, Sahin U, Gouttefangeas C, Britten CM, van der Burg SH. (2018)

Development of an RNA-based kit for easy generation of TCR-engineered lymphocytes to control T-cell assay performance.

J Immunol Methods. pii: S0022-1759(18)30025-5

DOI PMID

Schumacher J, Bacic T, Staritzbichler R, Daneschdar M, Klamp T, Arnold P, Jägle S, Türeci Ö, Markl J, Sahin U. (2018)

Enhanced stability of a chimeric hepatitis B core antigen virus-like-particle (HBcAg-VLP) by a C-terminal linker-hexahistidine-peptide.

J Nanobiotechnology. 16(1):39

DOI PMID

BACKGROUND: Virus-like-particles (VLPs) are attractive nanoparticulate scaffolds for broad applications in material/biological sciences and medicine. Prior their functionalization, specific adaptations have to be carried out. These adjustments frequently lead to disordered particles, but the particle integrity is an essential factor for the VLP suitability. Therefore, major requirements for particle stabilization exist. The objective of this study was to evaluate novel stabilizing elements for functionalized chimeric hepatitis B virus core antigen virus-like particles (HBcAg-VLP), with beneficial characteristics for vaccine development, imaging or delivery.‍RESULTS:The effects of a carboxy-terminal polyhistidine-peptide and an intradimer disulfide-bridge on the stability of preclinically approved chimeric HBcAg-VLPs were assessed. We purified recombinant chimeric HBcAg-VLPs bearing different modified C-termini and compared their physical and chemical particle stability by quantitative protein-biochemical and biophysical techniques. We observed lower chemical resistance of T = 3- compared to T = 4-VLP (triangulation number) capsids and profound impairment of accessibility of hexahistidine-peptides in assembled VLPs. Histidines attached to the C-terminus were associated with superior mechanical and/or chemical particle stability depending on the number of histidine moieties. A molecular modeling approach based on cryo-electron microscopy and biolayer interferometry revealed the underlying structural mechanism for the strengthening of the integrity of VLPs. Interactions triggering capsid stabilization occur on a highly conserved residue on the basis of HBcAg-monomers as well as on hexahistidine-peptides of adjacent monomers. This new stabilization mechanism appears to mimic an evolutionary conserved stabilization concept for hepadnavirus core proteins.CONCLUSIONS:These findings establish the genetically simply transferable C-terminal polyhistidine-peptide as a general stabilizing element for chimeric HBcAg-VLPs to increase their suitability.‍

Boegel S, Löwer M, Bukur T, Sorn P, Castle J, Sahin U. (2018)

HLA and proteasome expression body map.

BMC Medical Genomics. 11:36

DOI PMID

Background: The presentation of HLA peptide complexes to T cells is a highly regulated and tissue specific process involving multiple transcriptionally controlled cellular components. The extensive polymorphism of HLA genes and the complex composition of the proteasome make it difficult to map their expression profiles across tissues.Methods: Here we applied a tailored gene quantification pipeline to 4323 publicly available RNA-Seq datasets representing 55 normal tissues and cell types to examine expression profiles of (classical and non-classical) HLA class I, class II and proteasomal genes.Results: We generated the first comprehensive expression atlas of antigen presenting-related genes across 56 normal tissues and cell types, including immune cells, pancreatic islets, platelets and hematopoietic stem cells. We found a surprisingly heterogeneous HLA expression pattern with up to 100-fold difference in intra-tissue median HLA abundances. Cells of the immune system and lymphatic organs expressed the highest levels of classical HLA class I (HLA-A,-B,-C), class II (HLA-DQA1,-DQB1,-DPA1,-DPB1,-DRA,-DRB1) and non-classical HLA class I (HLA-E,-F) molecules, whereas retina, brain, muscle, megakaryocytes and erythroblasts showed the lowest abundance. In contrast, we identified a distinct and highly tissue-restricted expression pattern of the non-classical class I gene HLA-G in placenta, pancreatic islets, pituitary gland and testis. While the constitutive proteasome showed relatively constant expression across all tissues, we found the immunoproteasome to be enriched in lymphatic organs and almost absent in immune privileged tissues.Conclusions: Here, we not only provide a reference catalog of tissue and cell type specific HLA expression, but also highlight extremely variable expression of the basic components of antigen processing and presentation in different cell types. Our findings indicate that low expression of classical HLA class I molecules together with lack of immunoproteasome components as well as upregulation of HLA-G may be of key relevance to maintain tolerance in immune privileged tissues.

Sahin U, Türeci Ö. (2018)

Personalized vaccines for cancer immunotherapy.

Science. 359(6382):1355-1360.

DOI PMID

Shen L, Tenzer S, Storck W, Hobernik D, Raker VK, Fischer K, Decker S, Dzionek A, Krauthäuser S, Diken M, Nikolaev A, Maxeiner J, Schuster P, Kappel C, Verschoor A, Schild H, Grabbe S, Bros M. (2018)

Protein corona-mediated targeting of nanocarriers to B cells allows redirection of allergic immune responses.

J Allergy Clin Immunol. Jan 31. pii: S0091-6749(18)30121-0

DOI PMID

Background: Nanoparticle (NP)–based vaccines are attractive immunotherapy tools because of their capability to codeliver antigen and adjuvant to antigen-presenting cells. Their cellular distribution and serum protein interaction (“protein corona”) after systemic administration and their effect on the functional properties of NPs is poorly understood.‍Objectives: We analyzed the relevance of the protein corona on cell type–selective uptake of dextran-coated NPs and determined the outcome of vaccination with NPs that codeliver antigen and adjuvant in disease models of allergy.‍Methods: The role of protein corona constituents for cellular binding/uptake of dextran-coated ferrous nanoparticles (DEX-NPs) was analyzed both in vitro and in vivo. DEX-NPs conjugated with the model antigen ovalbumin (OVA) and immunostimulatory CpG-rich oligodeoxynucleotides were administered to monitor the induction of cellular and humoral immune responses. Therapeutic effects of this DEX-NP vaccine in mouse models of OVA-induced anaphylaxisand allergic asthma were assessed.‍Results: DEX-NPs triggered lectin-induced complement activation, yielding deposition of activated complement factor 3 on the DEX-NP surface. In the spleen DEX-NPs targeted predominantly B cells through complement receptors 1 and 2. The DEX-NP vaccine elicited much stronger OVA-specific IgG2a production than coadministered soluble OVA plus CpG oligodeoxynucleotides. B-cell binding of the DEX-NP vaccine was critical for IgG2aproduction. Treatment of OVA-sensitized mice with the DEX-NP vaccine prevented induction of anaphylactic shock and allergic asthma accompanied by IgE inhibition.‍Conclusions: Opsonization of lectin-coated NPs by activated complement components results in selective B-cell targeting. The intrinsic B-cell targeting property of lectin-coated NPs can be exploited for treatment of allergic immune responses

Diken M, Chu KK, Brodsky AN. (2018)

Translating Science into Survival: Report on the Third International Cancer Immunotherapy Conference.

Cancer Immunol Res. 6(1):10-13. doi: 10.1158/2326-6066.CIR-17-0656.

DOI PMID

Canli Ö, Nicolas AM, Gupta J, Finkelmeier F, Goncharova O, Pesic M, Neumann T, Horst D, Löwer M, Sahin U, Greten FR. (2017)

Myeloid Cell-Derived Reactive Oxygen Species Induce Epithelial Mutagenesis.

Cancer Cell. 2017. 32(6):869-883.

DOI PMID

Hutzler S, Erbar S, Jabulowsky RA, Hanauer JRH, Schnotz JH, Beissert T, Bodmer BS, Eberle R, Boller K, Klamp T, Sahin U, Mühlebach MD. (2017)

Antigen-specific oncolytic MV-based tumor vaccines through presentation of selected tumor-associated antigens on infected cells or virus-like particles.

Sci. Rep. 2017. 7(1):16892.

DOI PMID

Beissert T, Koste L, Perkovic M, Walzer KC, Erbar S, Selmi A, Diken M, Kreiter S, Türeci Ö, Sahin U. (2017)

Improvement of In Vivo Expression of Genes Delivered by Self-Amplifying RNA Using Vaccinia Virus Immune Evasion Proteins.

Hum. Gene Ther. 2017/09/06 online.

DOI PMID

Vogel AB, Lambert L, Kinnear E, Busse D, Erbar S, Reuter KC, Wicke L, Perkovic M, Beissert T, Haas H, Reece ST, Sahin U, Tregoning JS. (2017)

Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses.

Mol Ther. 2017 Dec 5. pii: S1525-0016(17)30594-4.

DOI PMID

Sahu SK, Tiwari N, Pataskar A, Zhuang Y, Borisova M, Diken M, Strand S, Beli P, Tiwari VK. (2017)

FBXO32 promotes microenvironment underlying epithelial-mesenchymal transition via CtBP1 during tumour metastasis and brain development.

Nat Commun. 2017 Nov 15;8(1):1523.

DOI PMID

Schulz H, Ruppert AK, Herms S, Wolf C, Mirza-Schreiber N, Stegle O, Czamara D, Forstner AJ, Sivalingam S, Schoch S, Moebus S, Pütz B, Hillmer A, Fricker N, Vatter H, Müller-Myhsok B, Nöthen MM, Becker AJ, Hoffmann P, Sander T, Cichon S. (2017)

Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus.

Nat Commun. 2017 Nov 15;8(1):1511.

DOI PMID

Stadler CR, Bahr-Mahmud H, Celik L, Hebich B, Roth AS, Roth RP, Kariko K, Tureci O, Sahin U. (2017)

Elimination of large tumors in mice by mRNA-encoded bispecific antibodies.

Nat Med. 2017.(7):815-817.

DOI PMID

Kong SL, Liu X, Suhaimi NM, Koh KJH, Hu M, Lee DYS, Cima I, Phyo WM, Lee EXW, Tai JA, Foong YM, Vo JH, Koh PK, Zhang T, Ying JY, Lim B, Tan MH, Hillmer AM. (2017)

Molecular characterization of circulating colorectal tumor cells defines genetic signatures for individualized cancer care.

Oncotarget. 2017; 8:68026-68037.

DOI PMID

Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Löwer M, Bukur V, Tadmor AD, Luxemburger U, Schrörs B, Omokoko T, Vormehr M, Albrecht C, Paruzynski A, Kuhn AN, Buck J, Heesch S, Schreeb KH, Müller F, Ortseifer I, Vogler I, Godehardt E, Attig S, Rae R, Breitkreuz A, Tolliver C, Suchan M, Martic G, Hohberger A, Sorn P, Diekmann J, Ciesla J, Waksmann O, Kemmer-Brück A, Witt M, Zillgen M, Rothermel A, Kasemann B, Langer D, Bolte S, Diken M, Kreiter S, Nemecek R, Gebhardt C, Grabbe S, Höller C, Utikal J, Huber C, Loquai C, Türeci Ö. (2017)

Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer.

Nature. 2017. 547(7662):222-226.

DOI PMID

Heilmann-Heimbach S, Herold C, Hochfeld LM, Hillmer AM, Nyholt DR, Hecker J, Javed A, Chew EG, Pechlivanis S, Drichel D, Heng XT, Del Rosario RC, Fier HL, Paus R, Rueedi R, Galesloot TE, Moebus S, Anhalt T, Prabhakar S, Li R, Kanoni S, Papanikolaou G, Kutalik Z, Deloukas P, Philpott MP, Waeber G, Spector TD, Vollenweider P, Kiemeney LA, Dedoussis G, Richards JB, Nothnagel M, Martin NG, Becker T, Hinds DA, Nöthen MM. (2017)

Meta-analysis identifies novel risk loci and yielads systemtic insights into the biology of male-pattern baldness.

Nat Commun. 2017 Mar 8;8:14694.

DOI PMID

Diken M, Kranz LM, Kreiter S, Sahin U. (2017)

mRNA: A Versatile Molecule for Cancer Vaccines.

Curr Issues Mol Biol. 2017;22:113-128.

DOI PMID

Diken M, Vormehr M, Grunwitz C, Kreiter S, Türeci Ö, Sahin U. (2017)

Discovery and Subtyping of Neo-Epitope Specific T-Cell Responses for Cancer Immunotherapy: Addressing the Mutanome.

Methods Mol Biol.2017;1499:223-236.

DOI PMID

Hinz T, Kallen K, Britten CM, Flamion B, Granzer U, Hoos A, Huber C, Khleif S, Kreiter S, Rammensee HG, Sahin U, Singh-Jasuja H, Türeci Ö, Kalinke U. (2017)

The European Regulatory Environment of RNA-Based Vaccines.

Methods Mol Biol. 2017;1499:203-222.

DOI PMID

Strenkowska M, Grzela R, Majewski M, Wnek K, Kowalska J, Lukaszewicz M, Zuberek J, Darzynkiewicz E, Kuhn AN, Sahin U, Jemielity J. (2016)

Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential.

Nucleic Acids Res. 2016 Nov 16; 44(20):9578-9590 Epub 2016 Oct 7.

DOI PMID

Grabbe S, Haas H, Diken M, Kranz LM, Langguth P, Sahin U. (2016)

Translating nanoparticulate-personalized cancer vaccines into clinical applications: case study with RNA-lipoplexes for the treatment of melanoma.

Nanomedicine (Lond) 2016 Oct 11.

DOI PMID

Waisman A, Hövelmeyer N, Diefenbach A, Schuppan D, Reddehase MJ, Kleinert H, Kaina B, Grabbe S, Galle PR, Theobald M, Zipp F, Sahin U, Türeci Ö, Kreiter S, Langguth P, Decker H, van Zandbergen G, Schild H. (2016)

Past, present and future of immunology in Mainz.

Cell Immunol 2016.

DOI PMID

Poschke I, Faryna M, Bergmann F, Flossdorf M, Lauenstein C, Hermes J, Hinz U, Hank T, Ehrenberg R, Volkmar M, Loewer M, Glimm H, Hackert T, Sprick MR, Höfer T, Trumpp A, Halama N, Hassel JC, Strobel O, Büchler M, Sahin U, Offringa R. (2016)

Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma.

Oncoimmunology 5(12):e1240859 2016 Oct 7

DOI PMID

McCann KJ, Mander A, Cazaly A, Chudley L, Stasakova J, Thirdborough SM, King A, Lloyd-Evans P, Buxton E, Edwards C, Halford S, Bateman A, O’Callaghan A, Clive S, Anthoney A, Jodrell DI, Weinschenk T, Simon P, Sahin U, Thomas GJ, Stevenson FK, Ottensmeier CH. (2016)

Targeting Carcinoembryonic Antigen with DNA Vaccination: On-Target Adverse Events Link with Immunological and Clinical Outcomes

Clinical Cancer Research 2016

DOI PMID

Liu Y, Loewer M, Aluru S, Schmidt B. (2016)

SNVSniffer: an integrated caller for germline and somatic single-nucleotide and indel mutations.

BMC Syst Biol. 2016 Aug 1;10 Suppl 2:47.

DOI PMID

BACKGROUND:Various approaches to calling single-nucleotide variants (SNVs) or insertion-or-deletion (indel) mutations have been developed based on next-generation sequencing (NGS). However, most of them are dedicated to a particular type of mutation, e.g. germline SNVs in normal cells, somatic SNVs in cancer/tumor cells, or indels only. In the literature, efficient and integrated callers for both germline and somatic SNVs/indels have not yet been extensively investigated.RESULTS:We present SNVSniffer, an efficient and integrated caller identifying both germline and somatic SNVs/indels from NGS data. In this algorithm, we propose the use of Bayesian probabilistic models to identify SNVs and investigate a multiple ungapped alignment approach to call indels. For germline variant calling, we model allele counts per site to follow a multinomial conditional distribution. For somatic variant calling, we rely on paired tumor-normal pairs from identical individuals and introduce a hybrid subtraction and joint sample analysis approach by modeling tumor-normal allele counts per site to follow a joint multinomial conditional distribution. A comprehensive performance evaluation has been conducted using a diversity of variant calling benchmarks. For germline variant calling, SNVSniffer demonstrates highly competitive accuracy with superior speed in comparison with the state-of-the-art FaSD, GATK and SAMtools. For somatic variant calling, our algorithm achieves comparable or even better accuracy, at fast speed, than the leading VarScan2, SomaticSniper, JointSNVMix2 and MuTect.CONCLUSIONS:SNVSniffers demonstrates the feasibility to develop integrated solutions to fast and efficient identification of germline and somatic variants. Nonetheless, accurate discovery of genetic variations is critical yet challenging, and still requires substantially more research efforts being devoted. SNVSniffer and synthetic samples are publicly available at http://snvsniffer.sourceforge.net.

Selmi A, Vascotto F, Kautz-Neu K, Türeci Ö, Sahin U, von Stebut E, Diken M, Kreiter S. (2016)

Uptake of synthetic naked RNA by skin-resident dendritic cells via macropinocytosis allows antigen expression and induction of T-cell responses in mice.

Cancer Immunol Immunother 2016 Jul 15.

DOI PMID

Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, Meng M, Fritz D, Vascotto F, Hefesha H, Grunwitz C, Vormehr M, Hüsemann Y, Selmi A, Kuhn AN, Buck J, Derhovanessian E, Rae R, Attig S, Diekmann J, Jabulowsky RA, Heesch S, Hassel J, Langguth P, Grabbe S, Huber C, Türeci Ö, Sahin U. (2016)

Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy.

Nature 2016-06-01; advance online publication

DOI PMID

Kreiter S, Diken M, Selmi A, Petschenka J, Türeci Ö, Sahin U. (2016)

FLT3 Ligand as a Molecular Adjuvant for Naked RNA Vaccines.

Methods Mol Biol. 2016;1428:163-75

DOI PMID

Alrefai H, Muhammad K, Rudolf R, Pham DA, Klein-Hessling S, Patra AK, Avots A, Bukur V, Sahin U, Tenzer S, Goebeler M, Kerstan A, Serfling E. (2016)

NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells.

Nat Commun. 2016 May 25;7:11724.

DOI PMID

Wirtz RM, Sihto H, Isola J, Heikkilä P, Kellokumpu-Lehtinen PL, Auvinen P, Turpeenniemi-Hujanen T, Jyrkkiö S, Lakis S, Schlombs K, Laible M, Weber S, Eidt S, Sahin U, Joensuu H. (2016)

Biological subtyping of early breast cancer: a study comparing RT-qPCR with immunohistochemistry.

Breast Cancer Res Treat. 2016 May 24

DOI PMID

The biological subtype of breast cancer influences the selection of systemic therapy. Distinction between luminal A and B cancers depends on consistent assessment of Ki-67, but substantial intra-observer and inter-observer variability exists when immunohistochemistry (IHC) is used. We compared RT-qPCR with IHC in the assessment of Ki-67 and other standard factors used in breast cancer subtyping. RNA was extracted from archival breast tumour tissue of 769 women randomly assigned to the FinHer trial. Cancer ESR1, PGR, ERBB2 and MKI67 mRNA content was quantitated with an RT-qPCR assay. Local pathologists assessed ER, PgR and Ki-67 expression using IHC. HER2 amplification was identified with chromogenic in situ hybridization (CISH) centrally. The results were correlated with distant disease-free survival (DDFS) and overall survival (OS). qPCR-based and IHC-based assessments of ER and PgR showed good concordance. Both low tumour MKI67 mRNA (RT-qPCR) and Ki-67 protein (IHC) levels were prognostic for favourable DDFS [hazard ratio (HR) 0.42, 95 % CI 0.25-0.71, P = 0.001; and HR 0.56, 0.37-0.84, P = 0.005, respectively] and OS. In multivariable analyses, cancer MKI67 mRNA content had independent influence on DDFS (adjusted HR 0.51, 95 % CI 0.29-0.89, P = 0.019) while Ki-67 protein expression had not any influence (P = 0.266) whereas both assessments influenced independently OS. Luminal B patients treated with docetaxel-FEC had more favourable DDFS and OS than those treated with vinorelbine-FEC when the subtype was defined by RT-qPCR (for DDFS, HR 0.52, 95 % CI 0.29-0.94, P = 0.031), but not when defined using IHC. Breast cancer subtypes approximated with RT-qPCR and IHC show good concordance, but cancer MKI67 mRNA content correlated slightly better with DDFS than Ki-67 expression. The findings based on MKI67 mRNA content suggest that patients with luminal B cancer benefit more from docetaxel-FEC than from vinorelbine-FEC.

Türeci Ö, Vormehr M, Diken M, Kreiter S, Huber C, Sahin U. (2016)

Targeting the Heterogeneity of Cancer with Individualized Neoepitope Vaccines.

Clinical Cancer Research 2016; 22(8):1885-96

DOI PMID

Knies D, Klobuch S, Xue SA, Birtel M, Echchannaoui H, Yildiz O, Omokoko T, Guillaume P, Romero P, Stauss H, Sahin U, Herr W, Theobald M, Thomas S, Voss RH. (2016)

An optimized single chain TCR scaffold relying on the assembly with the native CD3-complex prevents residual mispairing with endogenous TCRs in human T-cells.

Oncotarget 2016.

DOI PMID

Immunotherapy of cancer envisions the adoptive transfer of T-cells genetically engineered with tumor-specific heterodimeric α/β T-cell receptors (TCRα/β). However, potential mispairing of introduced TCRα/β-chains with endogenous β/α-ones may evoke unpredictable autoimmune reactivities. A novel single chain (sc)TCR format relies on the fusion of the Vα-Linker-Vβ-fragment to the TCR Cβ-domain and coexpression of the TCR Cα-domain capable of recruiting the natural CD3-complex for full and hence, native T-cell signaling. Here, we tested whether such a gp100(280-288)- or p53(264-272) tumor antigen-specific scTCR is still prone to mispairing with TCRα. In a human Jurkat-76 T-cell line lacking endogenous TCRs, surface expression and function of a scTCR could be reconstituted by any cointroduced TCRα-chain indicating mispairing to take place on a molecular basis. In contrast, transduction into human TCRα/β-positive T-cells revealed that mispairing is largely reduced. Competition experiments in Jurkat-76 confirmed the preference of dcTCR to selfpair and to spare scTCR. This also allowed for the generation of dc/scTCR-modified cytomegalovirus/tumor antigen-bispecific T-cells to augment T-cell activation in CMV-infected tumor patients. Residual mispairing was prevented by strenghtening the Vα-Li-Vβ-fragment through the design of a novel disulfide bond between a Vα- and a linker-resident residue close to Vβ. Multimer-stainings, and cytotoxicity-, IFNγ-secretion-, and CFSE-proliferation-assays, the latter towards dendritic cells endogenously processing RNA-electroporated gp100 antigen proved the absence of hybrid scTCR/TCRα-formation without impairing avidity of scTCR/Cα in T-cells. Moreover, a fragile cytomegalovirus pp65(495-503)-specific scTCR modified this way acquired enhanced cytotoxicity. Thus, optimized scTCR/Cα inhibits residual TCR mispairing to accomplish safe adoptive immunotherapy for bulk endogenous TCRα/β-positive T-cells.

Kreiter S, Diken M, Pascolo S, Nair SK, Thielemans KM, Geall A. (2016)

The RNA Vaccination Therapy: Advances in an Emerging Field.

Journal of Immunology Research 2016.

DOI PMID

After more than two decades of research, the efforts to translate the concept of RNA based vaccination have reached a critical mass. Several preclinical and clinical projects located in the academic or industrial setting are underway and the coming years will allow us to get broad insight into clinical feasibility, safety, and first efficacy data. It can be anticipated that some RNA based vaccines will be approved within the near future.The use of in vitro transcribed RNA is now viewed as an attractive approach for vaccination therapies, with several features contributing to its favorable characteristics. RNA allows expression of molecularly well-defined proteins and its half-life can be steered through modifications in the RNA backbone. Moreover, unlike DNA, RNA does not need to enter the nucleus during transfection and there is no risk of integration into the genome, assuring safety through transient activity. Rapid design and synthesis in response to demand, accompanied by inexpensive pharmaceutical production, are additional features facilitating its clinical translation.The seminal work of Wolff et al. which showed that RNA injected directly into skeletal muscle can lead to protein expression opened the era of RNA based therapeutics [1]. This observation was followed by Martinon et al. and Conry et al. who performed the first vaccinations with viral- and cancer-antigen encoding RNA, respectively, and elicited antigen-specific immune responses [2, 3]. RNA based vaccination was also carried out by ex vivo transfection of mRNA into autologous dendritic cells (DCs) which was initially described by Boczkowski et al. [4]. Along with the introduction of highly efficient transfection methods for RNA [5], several preclinical and clinical studies showed the safety and efficacy of this RNA based vaccination strategy [6]. In a different setting, Hoerr et al. proved that direct injection of naked or protamine-protected RNA intradermally can lead to induction of T cell and antibody responses in preclinical models and then translated the approach into a clinical setting [7–10]. Personalized cancer vaccination with RNA and intravenous delivery of liposome-complexed RNA [11, 12] are other recent promising strategies that have reached the clinical stage. In addition to cancer, other disease settings such as infectious diseases as well as allergy were also shown to benefit from RNA based vaccination [13–15].In this special issue, a number of papers will illustrate and summarize the advances in this emerging field. M. A. McNamara et al. will provide a comprehensive review on RNA based vaccines in cancer immunotherapy, which is further detailed for the use of mutanome engineered RNA by M. Vormehr et al. These will be complemented by a review from K. K. L. Phua describing targeted delivery systems for RNA based nanoparticle tumor vaccines. Other contributions will describe RNA based methods for in vitro analytics such as cytotoxicity (T. A. Omokoko et al.) or effects of RNA on transcriptome of DCs (S. Hoyer et al.). Finally, E. Hattinger et al. will also demonstrate, with a different disease focus, the efficacy of prophylactic RNA vaccination against allergy.In conclusion, this special issue covers many aspects of RNA based vaccines. As RNA based vaccination is not the only application of the RNA technology (RNA based protein replacement, immunomodulation, and cellular therapy are further promising fields of development), we hope to have sparked the readers interest in RNA based therapies in general.

Wagner M, Jung J, Koslowski M, Türeci Ö, Tiwari VK, Sahin U. (2016)

Chromatin Immunoprecipitation Assay to Identify Genomic Binding Sites of Regulatory Factors.

Methods in molecular biology (Clifton, N.J.) 2016, 1366:53-65.

DOI PMID

Kloke BP, Kreiter S, Vormehr M, Diken M, Kuhn AN, Sahin U. (2016)

Actively personalized cancer vaccines–the step into clinical application.

Pharmazie 2016, 1:43-7.

DOI PMID

Omokoko TA, Luxemburger U, Bardissi S, Simon P, Utsch M, Breitkreuz A, Türeci Ö, Sahin U. (2016)

Luciferase mRNA Transfection of Antigen Presenting Cells Permits Sensitive Nonradioactive Measurement of Cellular and Humoral Cytotoxicity.

J Immunol Res 2016, 2016:9540975.

DOI PMID

Vormehr M, Schrörs B, Boegel S, Löwer M, Türeci Ö, Sahin U. (2015)

Mutanome Engineered RNA Immunotherapy: Towards Patient-Centered Tumor Vaccination.

Journal of Immunology Research 2015, 2015:1-6.

DOI

Vormehr M, Diken M, Boegel S, Kreiter S, Türeci Ö, Sahin U. (2015)

Mutanome directed cancer immunotherapy.

Current opinion in immunology 2015, 39:14-22.

DOI PMID

Stadler CR, Bähr-Mahmud H, Plum LM, Schmoldt K, Kölsch AC, Türeci Ö, Sahin U. (2015)

Characterization of the first-in-class T-cell-engaging bispecific single-chain antibody for targeted immunotherapy of solid tumors expressing the oncofetal protein claudin 6.

OncoImmunology 2015, 5:e1091555.

DOI PMID

Malczyk AH, Kupke A, Prüfer S, Scheuplein VA, Hutzler S, Kreuz D, Beissert T, Bauer S, Hubich-Rau S, Tondera C, Eldin HS, Schmidt J, Vergara-Alert J, Süzer Y, Seifried J, Hanschmann K, Kalinke U, Herold S, Sahin U, Cichutek K, Waibler Z, Eickmann M, Becker S, Mühlebach MD. (2015)

A Highly Immunogenic and Protective Middle East Respiratory Syndrome Coronavirus Vaccine Based on a Recombinant Measles Virus Vaccine Platform.

Journal of virology 2015, 89:11654-11667.

DOI PMID

In 2012, the first cases of infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) were identified. Since then, more than 1,000 cases of MERS-CoV infection have been confirmed; infection is typically associated with considerable morbidity and, in approximately 30% of cases, mortality. Currently, there is no protective vaccine available. Replication-competent recombinant measles virus (MV) expressing foreign antigens constitutes a promising tool to induce protective immunity against corresponding pathogens. Therefore, we generated MVs expressing the spike glycoprotein of MERS-CoV in its full-length (MERS-S) or a truncated, soluble variant of MERS-S (MERS-solS). The genes encoding MERS-S and MERS-solS were cloned into the vaccine strain MVvac2 genome, and the respective viruses were rescued (MVvac2-CoV-S and MVvac2-CoV-solS). These recombinant MVs were amplified and characterized at passages 3 and 10. The replication of MVvac2-CoV-S in Vero cells turned out to be comparable to that of the control virus MVvac2-GFP (encoding green fluorescent protein), while titers of MVvac2-CoV-solS were impaired approximately 3-fold. The genomic stability and expression of the inserted antigens were confirmed via sequencing of viral cDNA and immunoblot analysis. In vivo, immunization of type I interferon receptor-deficient (IFNAR−/−)-CD46Ge mice with 2 × 105 50% tissue culture infective doses of MVvac2-CoV-S(H) or MVvac2-CoV-solS(H) in a prime-boost regimen induced robust levels of both MV- and MERS-CoV-neutralizing antibodies. Additionally, induction of specific T cells was demonstrated by T cell proliferation, antigen-specific T cell cytotoxicity, and gamma interferon secretion after stimulation of splenocytes with MERS-CoV-S presented by murine dendritic cells. MERS-CoV challenge experiments indicated the protective capacity of these immune responses in vaccinated mice.

Diken M, Kreiter S, Kloke B, Sahin U. (2015)

Current Developments in Actively Personalized Cancer Vaccination with a Focus on RNA as the Drug Format.

Progress in tumor research 2015, 42:44-54.

DOI PMID

Poleganov MA, Eminli S, Beissert T, Herz S, Moon J, Goldmann J, Beyer A, Heck R, Burkhart I, Barea Roldan D, Türeci Ö, Yi K, Hamilton B, Sahin U. (2015)

Efficient Reprogramming of Human Fibroblasts and Blood-Derived Endothelial Progenitor Cells Using Nonmodified RNA for Reprogramming and Immune Evasion.

Human Gene Therapy 2015, 26:751-766.

DOI PMID

Paret C, Simon P, Vormbrock K, Bender C, Kölsch A, Breitkreuz A, Yildiz Ö, Omokoko T, Hubich-Rau S, Hartmann C, Häcker S, Wagner M, Roldan DB, Selmi A, Türeci Ö, Sahin U. (2015)

CXorf61 is a target for T cell based immunotherapy of triple-negative breast cancer.

Oncotarget 2015, 6:25356-25367.

DOI PMID

Kuemmel A, Simon P, Breitkreuz A, Röhlig J, Luxemburger U, Elsäßer A, Schmidt LH, Sebastian M, Sahin U, Türeci Ö, Buhl R. (2015)

Humoral immune responses of lung cancer patients against the Transmembrane Phosphatase with TEnsin homology (TPTE).

Lung Cancer. 2015 Nov;90(2):334-41.

DOI PMID

Jiménez Calvente C, Sehgal A, Popov Y, Kim YO, Zevallos V, Sahin U, Diken M, Schuppan D. (2015)

Specific hepatic delivery of procollagen α1(I) small interfering RNA in lipid-like nanoparticles resolves liver fibrosis.

Hepatology (Baltimore, Md.) 2015, 62:1285-1297.

DOI PMID

Kranz LM, Birtel M, Krienke C, Grunwitz C, Petschenka J, Reuter KC, van de Roemer N, Vascotto F, Vormehr M, Kreiter S, Diken M. (2016)

CIMT 2015: The right patient for the right therapy – Report on the 13th annual meeting of the Association for Cancer Immunotherapy.

Human vaccines & immunotherapeutics 2016, 12:213-221. DE

DOI PMID

Bidmon N, Attig S, Rae R, Schröder H, Omokoko TA, Simon P, Kuhn AN, Kreiter S, Sahin U, Gouttefangeas C, van der Burg, Sjoerd H, Britten CM. (2015)

Generation of TCR-engineered T cells and their use to control the performance of T cell assays.

Journal of immunology (Baltimore, Md.: 1950) 2015, 194:6177-6189.

DOI

White S, Laske K, Welters MJ, Bidmon N, van der Burg, Sjoerd H, Britten CM, Enzor J, Staats J, Weinhold KJ, Gouttefangeas C, Chan C. (2014)

Managing Multi-center Flow Cytometry Data for Immune Monitoring.

Cancer informatics 2014, 13:111-122.

DOI PMID

Vallazza B, Petri S, Poleganov MA, Eberle F, Kuhn AN, Sahin U. (2015)

Recombinant messenger RNA technology and its application in cancer immunotherapy, transcript replacement therapies, pluripotent stem cell induction, and beyond.

Wiley interdisciplinary reviews. RNA 2015, 6:471-499.

DOI PMID

Maaß F, Wüstehube-Lausch J, Dickgießer S, Valldorf B, Reinwarth M, Schmoldt H, Daneschdar M, Avrutina O, Sahin U, Kolmar H. (2015)

Cystine-knot peptides targeting cancer-relevant human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).

Journal of peptide science: an official publication of the European Peptide Society 2015, 21:651-660.

DOI PMID

Kreiter S, Vormehr M, van de Roemer, Niels, Diken M, Löwer M, Diekmann J, Boegel S, Schrörs B, Vascotto F, Castle JC, Tadmor AD, Schoenberger SP, Huber C, Türeci Ö, Sahin U. (2015)

Mutant MHC class II epitopes drive therapeutic immune responses to cancer.

Nature 2015, 520:692-696.

DOI PMID

Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient’s tumour possesses a unique set of mutations (‘the mutanome’) that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient’s individual tumour-specific mutations1. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4+ T cells. Vaccination with such CD4+ immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that CD4+ T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient’s tumour with vaccines produced ‘just in time’.

Foerster F, Strobl S, Kaps L, Weng S, Kim YO, Bros M, Diken M, Boegel S, Castle J, Bockamp E, Schuppan D. (2015)

P0311. Balb/c and C57/Bl6 mice exhibit differences in their susceptibility and anti-tumor response to B16F10 melanoma liver metastasis.

Journal of Hepatology 2015, 62:S425.

DOI

While progress has been made in increasing survival rates in neoplasms detected at early stages, the prognosis of metastasized tumors remains dismal. Liver metastases in particular are survival-limiting in a broad range of malignancies. Therefore, a better understanding of the mechanisms that underlie (liver) metastasis is essential for improving cancer patients’ outcome. The B16F10 melanoma cell line is a well described cancer cell line with high metastatic potential that has been successfully used for human anti-cancer drug development. Since the B16F10 cell line has very low expression of MHC class I molecules, it is predestined for studying the innate anti-tumor immune response. We administered B16F10 cells stably transfected with a luciferase-expressing lentivirus via intrasplenic injection to induce liver metastasis in two different strains of wild-type mice. Bioluminescence was recorded 7 and 14 days after injection using an IVIS in vivo imaging system. 2 weeks after injection, mice were sacrificed and their metastatic burden measured. Liver probes were analysed with regard to immune cell populations and markers of M1-/M2-polarization by FACS, RT-qPCR and IHC. Whole transcriptome sequencing was performed on selected samples and their differential gene expression analysed. Within 2 weeks, mice developed severe metastatic disease. Notably, the allogeneic mouse strain (Balb/c) was more susceptible to B16F10 liver metastasis than the syngeneic strain (C57/Bl6). Metastasized livers showed a pattern of predominantly innate immunity with macrophages representing the major immune cell population. Interestingly, Balb/c mice exhibited a pattern of M1-, while C57/Bl6 mice showed a pattern of M2-macrophage polarization. Complete RNA sequencing of metastasized liver samples demonstrated that interferon-g and its downstream pathway (which is usually associated with an anti-tumor response) was significantly overexpressed in Balb/c mice, whereas the Tgfbeta pathway (which is considered immunosuppressive) was significantly upregulated in C57/Bl6 mice.The B16F10 melanoma liver metastasis model allows to study the innate immune response to invading cancer cells in the liver. The two wild-type mouse strains, Balb/c and C57/Bl6, appear to differ dramatically in their immunological anti-tumor responses, which is currently further explored.

Kang B, Okwieka P, Schöttler S, Seifert O, Kontermann RE, Pfizenmaier K, Musyanovych A, Meyer R, Diken M, Sahin U, Mailänder V, Wurm FR, Landfester K. (2015)

Tailoring the stealth properties of biocompatible polysaccharide nanocontainers.

Biomaterials 2015, 49:125-134.

DOI PMID

Omokoko T, Simon P, Türeci Ö, Sahin U. (2015)

Retrieval of functional TCRs from single antigen-specific T cells: Toward individualized TCR-engineered therapies.

Oncoimmunology 2015, 4:e1005523.

DOI PMID

Boegel S, Scholtalbers J, Löwer M, Sahin U, Castle JC. (2015)

In Silico HLA Typing Using Standard RNA-Seq Sequence Reads.

Methods in molecular biology (Clifton, N.J.) 2015, 1310:247-258.

DOI PMID

Scholtalbers J, Boegel S, Bukur T, Byl M, Goerges S, Sorn P, Loewer M, Sahin U, Castle JC. (2015)

TCLP: an online cancer cell line catalogue integrating HLA type, predicted neo-epitopes, virus and gene expression.

Genome medicine 2015, 7:118.

DOI PMID

Kloke B, Mahr A, Jabulowsky RA, Kutscher S, Rae R, Britten CM. (2014)

Cancer immunotherapy achieves breakthrough status: 12th annual meeting of the association for cancer immunotherapy (CIMT), Mainz, Germany, May 6-8, 2014.

Cancer immunology, immunotherapy: CII 2015, 64:923-930.

DOI PMID

Simon P, Omokoko TA, Breitkreuz A, Hebich L, Kreiter S, Attig S, Konur A, Britten CM, Paret C, Dhaene K, Tureci Ö, Sahin U. (2014)

Functional TCR retrieval from single antigen-specific human T cells reveals multiple novel epitopes.

Cancer Immunology Research 2 (12) (2014) 1230–1244.

DOI PMID

Diken M, Boegel S, Grunwitz C, Kranz LM, Reuter K, van de Roemer, Niels, Vascotto F, Vormehr M, Kreiter S. (2014)

CIMT 2014: Next waves in cancer immunotherapy–report on the 12th annual meeting of the Association for Cancer Immunotherapy: May 6–8 2014, Mainz, Germany.

Human vaccines & immunotherapeutics 2014, 10:3090-3100.

DOI PMID

Boegel S, Löwer M, Bukur T, Sahin U, Castle JC. (2014)

A catalog of HLA type, HLA expression, and neo-epitope candidates in human cancer cell lines.

Oncoimmunology 2014, 3:e954893.

DOI PMID

Boisguérin V, Castle JC, Loewer M, Diekmann J, Mueller F, Britten CM, Kreiter S, Türeci Ö, Sahin U. (2014)

Translation of genomics-guided RNA-based personalised cancer vaccines: towards the bedside.

Br J Cancer 2014, 111:1469-1475.

DOI PMID

Hadrup SR, Maurer D, Laske K, Frøsig TM, Andersen SR, Britten CM, van der Burg, Sjoerd H, Walter S, Gouttefangeas C. (2014)

Cryopreservation of MHC multimers: Recommendations for quality assurance in detection of antigen specific T cells.

Cytometry. Part A: the journal of the International Society for Analytical Cytology 2015, 87:37-48.

DOI PMID

Sahin U, Kariko K, Tureci O. (2014)

mRNA-based therapeutics–developing a new class of drugs.

Nature Reviews Drug Discovery 13 (10) (2014) 759–780.

DOI

Muhammad K, Alrefai H, Marienfeld R, Pham, Duong Anh Thuy, Murti K, Patra AK, Avots A, Bukur V, Sahin U, Kondo E, Klein-Hessling S, Serfling E. (2014)

NF-κB factors control the induction of NFATc1 in B lymphocytes.

European journal of immunology 2014, 44:3392-3402.

DOI PMID

Kuehnle M, Attig S, Britten CM, Schulze-Bergkamen H, Lordick F, Wichert G von, Thuss-Patience P, Stein A, Schuler M, Bassermann F, Sahin U, Türeci O. (2014)

Phenotyping of peripheral blood mononuclear cells of patients with advanced heavily pre-treated adenocarcinoma of the stomach and gastro-esophageal junction.

Cancer immunology, immunotherapy: CII 2014, 63:1273-1284.

DOI

Kreiter S, Castle JC, Türeci O, Sahin U. (2012)

Targeting the tumor mutanome for personalized vaccination therapy.

Oncoimmunology 2012, 1:768-769.

DOI PMID

Kowalska J, Wypijewska del Nogal, Anna, Darzynkiewicz ZM, Buck J, Nicola C, Kuhn AN, Lukaszewicz M, Zuberek J, Strenkowska M, Ziemniak M, Maciejczyk M, Bojarska E, Rhoads RE, Darzynkiewicz E, Sahin U, Jemielity J. (2014)

Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes.

Nucleic acids research 2014, 42:10245-10264.

DOI PMID

Chudley L, McCann KJ, Coleman A, Cazaly AM, Bidmon N, Britten CM, van der Burg, Sjoerd H, Gouttefangeas C, Jandus C, Laske K, Maurer D, Romero P, Schröder H, Stynenbosch, Linda F M, Walter S, Welters, Marij J P, Ottensmeier CH. (2014)

Harmonisation of short-term in vitro culture for the expansion of antigen-specific CD8(+) T cells with detection by ELISPOT and HLA-multimer staining.

Cancer immunology, immunotherapy: CII 2014, 63:1199-1211.

DOI PMID

Reuter S, Martin H, Beckert H, Bros M, Montermann E, Belz C, Heinz A, Ohngemach S, Sahin U, Stassen M, Buhl R, Eshkind L, Taube C. (2014)

The Wnt/β-catenin pathway attenuates experimental allergic airway disease.

Journal of immunology (Baltimore, Md.: 1950) 2014, 193:485-495.

DOI PMID

Schumacher T, Bunse L, Pusch S, Sahm F, Wiestler B, Quandt J, Menn O, Osswald M, Oezen I, Ott M, Keil M, Balß J, Rauschenbach K, Grabowska AK, Vogler I, Diekmann J, Trautwein N, Eichmüller SB, Okun J, Stevanović S, Riemer AB, Sahin U, Friese MA, Beckhove P, Deimling A von, Wick W, Platten M. (2014)

A vaccine targeting mutant IDH1 induces antitumour immunity.

Nature 2014, 512:324-327.

DOI

Janetzki S, Britten CM. (2014)

The role of the reporting framework MIATA within current efforts to advance immune monitoring.

Journal of immunological methods 2014, 409:6-8.

DOI PMID

Castle JC, Loewer M, Boegel S, Tadmor AD, Boisguerin V, Graaf J de, Paret C, Diken M, Kreiter S, Türeci Ö, Sahin U. (2014)

Mutated tumor alleles are expressed according to their DNA frequency.

Scientific reports 2014, 4:4743.

DOI PMID

Koste L, Beissert T, Hoff H, Pretsch L, Türeci Ö, Sahin U. (2014)

T-cell receptor transfer into human T cells with ecotropic retroviral vectors.

Gene Therapy 21 (5) (2014) 533-538.

DOI PMID

Micke P, Mattsson, Johanna Sofia Margareta, Edlund K, Lohr M, Jirström K, Berglund A, Botling J, Rahnenfuehrer J, Marincevic M, Pontén F, Ekman S, Hengstler J, Wöll S, Sahin U, Türeci O. (2014)

Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer.

International journal of cancer. Journal international du cancer 2014, 135:2206-2214.

DOI PMID

Castle JC, Loewer M, Boegel S, Graaf J de, Bender C, Tadmor AD, Boisguerin V, Bukur T, Sorn P, Paret C, Diken M, Kreiter S, Türeci Ö, Sahin U. (2014)

Immunomic, genomic and transcriptomic characterization of CT26 colorectal carcinoma.

BMC genomics 2014, 15:190.

DOI PMID

Schnatbaum K, Schmoldt H, Daneschdar M, Plum LM, Jansong J, Zerweck J, Kühne Y, Masch A, Wenschuh H, Fiedler M, Türeci Ö, Sahin U, Reimer U. (2014)

Peptide microarrays enable rapid mimotope optimization for pharmacokinetic analysis of the novel therapeutic antibody IMAB362.

Biotechnology journal 2014, 9:545-554.

DOI PMID

Diken M, Kreiter S, Vascotto F, Selmi A, Attig S, Diekmann J, Huber C, Türeci Ö, Sahin U. (2013)

mTOR inhibition improves antitumor effects of vaccination with antigen-encoding RNA.

Cancer immunology research 2013, 1:386-392.

DOI

Wagner M, Koslowski M, Paret C, Schmidt M, Türeci O, Sahin U. (2013)

NCOA3 is a selective co-activator of estrogen receptor α-mediated transactivation of PLAC1 in MCF-7 breast cancer cells.

BMC cancer 2013, 13:570.

DOI PMID

Wöll, S., Schlitter, A.M., Dhaene, K., Roller, M., Esposito, I., Sahin, U., Türeci, Ö. (2013)

Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms.

Int J Cancer. 2013 Jul 30.

DOI PMID

Kloke B, Rae R, Mahr A, Burkhardt UE, Kvistborg P, Britten CM. (2013)

Toward the next waves of cancer immunotherapy: 11th Annual Meeting of the Association for Cancer Immunotherapy (CIMT), Mainz, Germany, May 14-16, 2013.

Cancer immunology, immunotherapy: CII 2014, 63:749-755.

DOI PMID

Britten CM, Singh-Jasuja H, Flamion B, Hoos A, Huber C, Kallen K, Khleif SN, Kreiter S, Nielsen M, Rammensee H, Sahin U, Hinz T, Kalinke U. (2013)

The regulatory landscape for actively personalized cancer immunotherapies.

Nature biotechnology 2013, 31:880-882.

DOI PMID

Cabezas-Wallscheid N, Eichwald V, Graaf J de, Löwer M, Lehr H, Kreft A, Eshkind L, Hildebrandt A, Abassi Y, Heck R, Dehof AK, Ohngemach S, Sprengel R, Wörtge S, Schmitt S, Lotz J, Meyer C, Kindler T, Zhang D, Kaina B, Castle JC, Trumpp A, Sahin U, Bockamp E. (2013)

Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model.

EMBO Mol Med 2013, 5:1804-1820.

DOI PMID

Britten CM, Walter S, Janetzki S. (2013)

Immunological Monitoring to Rationally Guide AAV Gene Therapy.

Frontiers in immunology 2013, 4:273.

DOI

McNeil LK, Price L, Britten CM, Jaimes M, Maecker H, Odunsi K, Matsuzaki J, Staats JS, Thorpe J, Yuan J, Janetzki S. (2013)

A harmonized approach to intracellular cytokine staining gating: Results from an international multiconsortia proficiency panel conducted by the Cancer Immunotherapy Consortium (CIC/CRI).

Cytometry 2013, 83A:728-738.

DOI

Diken M, Attig S, Grunwitz C, Kranz L, Simon P, van de Roemer, Niels, Vascotto F, Kreiter S. (2013)

CIMT 2013: advancing targeted therapies–report on the 11th Annual Meeting of the Association for Cancer Immunotherapy, May 14-16 2013, Mainz, Germany.

Human vaccines & immunotherapeutics 2013, 9:2025-2032.

DOI

Sahin U, Türeci O. (2013)

Antigen identification using SEREX.

Methods in molecular biology (Clifton, N.J.) 2013, 1061:59-77.

DOI PMID

Cron A, Gouttefangeas C, Frelinger J, Lin L, Singh SK, Britten CM, Welters MJP, van der Burg, Sjoerd H., West M, Chan C, Altan-Bonnet G. (2013)

Hierarchical Modeling for Rare Event Detection and Cell Subset Alignment across Flow Cytometry Samples.

PLoS Comput Biol 2013, 9:e1003130.

DOI

.Warminski M, Kowalska J, Buck J, Zuberek J, Lukaszewicz M, Nicola C, Kuhn AN, Sahin U, Darzynkiewicz E, Jemielity J (2013)

The synthesis of isopropylidene mRNA cap analogs modified with phosphorothioate moiety and their evaluation as promoters of mRNA translation.

Bioorganic & medicinal chemistry letters 2013, 23:3753-3758.

DOI PMID

Neufert C, Becker C, Türeci Ö, Waldner MJ, Backert I, Floh K, Atreya I, Leppkes M, Jefremow A, Vieth M, Schneider-Stock R, Klinger P, Greten FR, Threadgill DW, Sahin U, Neurath MF. (2013)

Tumor fibroblast-derived epiregulin promotes growth of colitis-associated neoplasms through ERK.

The Journal of clinical investigation 2013, 123:1428-1443.

DOI PMID

Scholtalbers J, Rößler J, Sorn P, Graaf J de, Boisguérin V, Castle J, Sahin U. (2013)

Galaxy LIMS for next-generation sequencing.

Bioinformatics (Oxford, England) 2013, 29:1233-1234.

DOI PMID

Schröder JC, Läßig AK, Galetzka D, Peters A, Castle JC, Diederich S, Zechner U, Müller-Forell W, Keilmann A, Bartsch O. (2013)

A boy with homozygous microdeletion of NEUROG1 presents with a congenital cranial dysinnervation disorder [Moebius syndrome variant].

Behavioral and brain functions: BBF 2013, 9:7.

DOI PMID

Kloke B, Kutscher S, Rae R, Kvistborg P, Britten CM, Hadrup SR. (2013)

oward next-generation cancer immunotherapy: 10th annual meeting of the Association for Cancer Immunotherapy (CIMT), Mainz, Germany, May 23-25, 2012.

Cancer immunology, immunotherapy: CII 2013, 62:975-981.

DOI

Janetzki S, Hoos A, Melief, Cornelis J M, Odunsi K, Romero P, Britten CM. (2013)

Structured reporting of T cell assay results.

Cancer immunity 2013, 13:13.

DOI

Boegel S, Löwer M, Schäfer M, Bukur T, Graaf J de, Boisguérin V, Türeci O, Diken M, Castle JC, Sahin U. (2012)

HLA typing from RNA-Seq sequence reads.

Genome medicine 2012, 4:102.

DOI PMID

Filbert H, Attig S, Bidmon N, Renard BY, Janetzki S, Sahin U, Welters, Marij J P, Ottensmeier C, van der Burg, Sjoerd H, Gouttefangeas C, Britten CM. (2012)

Serum-free freezing media support high cell quality and excellent ELISPOT assay performance across a wide variety of different assay protocols.

Cancer immunology, immunotherapy: CII 2013, 62:615-627.

DOI

Diken M, Kreiter S, Selmi A, Türeci O, Sahin U. (2012)

Antitumor vaccination with synthetic mRNA: strategies for in vitro and in vivo preclinical studies.

Methods in molecular biology (Clifton, N.J.) 2013, 969:235-246.

DOI PMID

Grudzien-Nogalska E, Kowalska J, Su W, Kuhn AN, Slepenkov SV, Darzynkiewicz E, Sahin U, Jemielity J, Rhoads RE. (2012)

Synthetic mRNAs with superior translation and stability properties.

Methods in molecular biology (Clifton, N.J.) 2013, 969:55-72.

DOI

Galon J, Pagès F, Marincola FM, Angell HK, Thurin M, Lugli A, Zlobec I, Berger A, Bifulco C, Botti G, Tatangelo F, Britten CM, Kreiter S, Chouchane L, Delrio P, Arndt H, Asslaber M, Maio M, Masucci GV, Mihm M, Vidal-Vanaclocha F, Allison JP, Gnjatic S, Hakansson L, Huber C, Singh-Jasuja H, Ottensmeier C, Zwierzina H, Laghi L, Grizzi F et al. (2012)

Cancer classification using the Immunoscore: a worldwide task force.

J Transl Med 2012, 10:205.

DOI PMID

Löwer M, Renard BY, Graaf J de, Wagner M, Paret C, Kneip C, Türeci O, Diken M, Britten C, Kreiter S, Koslowski M, Castle JC, Sahin U. (2012)

Confidence-based somatic mutation evaluation and prioritization.

PLoS computational biology 2012, 8:e1002714.

DOI PMID

Diekmann, J., Löwer, M., Castle, J.C., Kreiter, S., Türeci, Ö., Sahin, U. (2012)

The T Cell Druggable Genome.

European Pharmaceutical Review. Vol. 17. Issue 4. 2012.

DOI

Hoetker, M.S., Kiesslich, R., Diken, M., Moehler,M., Galle, P.R., Li, Y., Goetz, M. (2012)

Molecular in vivo imaging of gastric cancer in a human-murine xenograft model: targeting epidermal growth factor receptor.

Gastrointestinal Endoscopy. July 7, 2012.

DOI PMID

Britten, C.M., Janetzki, S., Butterfield, L.H., Ferrari, G., Gouttefangeas, C., Huber, C., Kalos, M., Levitsky, H.I., Maecker, H.T., Melief, C.J., O’Donnell-Tormey, J., Odunsi, K., Old, L.J., Ottenhoff, T.H., Ottensmeier, C., Pawelec, G., Roederer, M., Roep, B.O., Romero, P., van der Burg, S.H., Walter, S., Hoos, A., Davis, M.M. (2012)

T Cell Assays and MIATA: The Essential Minimum for Maximum Impact.

Immunity. 2012 Jul 27;37(1):1-2.

DOI PMID

Welters, M.J., Gouttefangeas, C., Ramwadhdoebe, T.H., Letsch, A., Ottensmeier, C.H., Britten, C.M., van der Burg, S.H. (2012)

Harmonization of the intracellular cytokine staining assay.

Cancer Immunol Immunother. 2012 Jul;61(7):967-78.

DOI PMID

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Britten CM, Janetzki S, van der Burg, S H, Huber C, Kalos M, Levitsky HI, Maecker HT, Melief, C J M, O’Donnell-Tormey J, Odunsi K, Old LJ, Pawelec G, Roep BO, Romero P, Hoos A, Davis MM. (2010)

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Tang ST, van Meijgaarden, Krista E, Caccamo N, Guggino G, Klein MR, van Weeren P, Kazi F, Stryhn A, Zaigler A, Sahin U, Buus S, Dieli F, Lund O, Ottenhoff, Tom H M. (2010)

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Mander A, Gouttefangeas C, Ottensmeier C, Welters, M J P, Low L, van der Burg, S H, Britten CM. (2010)

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