Publications

Scientific excellence is not an end in itself, but is a crucial tool for efficient translation of new ideas into viable solutions.

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2022

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.

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The B.1.1.529 (Omicron) SARS-CoV-2variant has raised global concerns due to its high number of mutations and itsrapid spread. It is of major importance to understand the impact of thisvariant on the acquired and induced immunity. Several preliminary studies havereported the impact of antibody binding and to this date, there are few studieson Omicron’s CD8+ T-cell immune escape.

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.

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Gliomas are intrinsic brain tumors witha high degree of constitutive and acquired resistance to standard therapeuticmodalities such as radiotherapy and alkylating chemotherapy. Glioma subtypesare recognized by characteristic mutations. Some of these characteristicmutations have shown to generate immunogenic neoepitopes suitable for targetedimmunotherapy.

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.

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Immune checkpoint inhibitors (ICI)targeting the PD-1/PD-L1 axis have changed the treatment paradigm for advancedsolid tumors; however, many patients experience treatment resistance. Inpreclinical models 4-1BB co-stimulation synergizes with ICI by activatingcytotoxic T- and NK-cell-mediated anti-tumor immunity. Here we characterize themechanism of action of a mouse-reactive Fc-inert PD-L1×4-1BB bispecificantibody (mbsAb-PD-L1×4-1BB) and provide proof-of-concept for enhancedanti-tumor activity. In reporter assays mbsAb-PD-L1×4-1BB exhibited conditional4-1BB agonist activity that was dependent on simultaneous binding to PD-L1.mbsAb-PD-L1×4-1BB further blocked the PD-L1/PD-1 interaction independently of4-1BB binding. By combining both mechanisms, mbsAb-PD-L1×4-1BB stronglyenhanced T-cell proliferation, cytokine production and antigen-specificcytotoxicity using primary mouse cells in vitro. Furthermore,mbsAb-PD-L1×4-1BB exhibited potent anti-tumor activity in the CT26 and MC38models in vivo, leading to the rejection of CT26 tumors that wereunresponsive to PD-L1 blockade alone. Anti-tumor activity was associated withincreased tumor-specific CD8+ T cells and reduced regulatory T cells within the tumormicroenvironment and tumor-draining lymph nodes. In immunocompetent tumor-freemice, mbsAb-PD-L1×4-1BB treatment neither induced T-cell infiltration into theliver nor elevated liver enzymes in the blood. Dual targeting of PD-L1 and4-1BB with a bispecific antibody may therefore address key limitations of firstgeneration 4-1BB-agonistic antibodies, and may provide a novel approach toimprove PD-1/PD-L1 checkpoint blockade.

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.

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Cancer therapy is an emergent application formRNA therapeutics. While in tumor immunotherapy, mRNA encoding fortumor-associated antigens is delivered to antigen-presenting cells in spleenand lymph nodes, other therapeutic options benefit from immediate delivery ofmRNA nanomedicines directly to the tumor. However, tumor targeting of mRNAtherapeutics is still a challenge, since, in addition to delivery of the cargoto the tumor, specifics of the targeted cell type as well as its interplay withthe tumor microenvironment are crucial for successful intervention. This studyinvestigated lipoplex nanoparticle-mediated mRNA delivery to spheroid cellculture models of melanoma. Insights into cell-type specific targeting,non-cell-autonomous effects, and penetration capacity in tumor and stroma cellsof the mRNA lipoplex nanoparticles were obtained. It was shown that bothcoculture of different cell types as well as three-dimensional cell growthcharacteristics can modulate distribution and transfection efficiency of mRNAlipoplex formulations. The results demonstrate that three-dimensional coculturespheroids can provide a valuable surplus of information in comparison toadherent cells. Thus, they may represent in vitro models with enhancedpredictivity for the in vivo activity of cancer nanotherapeutics.

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.

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SignificanceFibrosis is a consequence ofmost chronic liver diseases, but currently no approved antifibrotic treatmentis available. M2-type macrophages drive fibrosis progression and preventregression, even when effective causal therapies have been employed. M2-typemacrophages activate a cascade of fibrogenic effector cells and can preventremoval of excess scar tissue. To switch these profibrogenic M2 to fibrolytic(regenerative) macrophages, we developed a pH-degradable, nanogel-baseddelivery system which can be covalently functionalized with themacrophage-repolarizing bisphosphonate alendronate. The nanogels efficientlydeliver the clinically approved drug into hepatic nonparenchymal cells afterintravenous administration. They do not eliminate macrophages but repolarizetheir phenotype and subsequently block fibrosis progression. This approachestablishes a nanotherapeutic delivery platform to treat further M2-typemacrophage-driven diseases, including cancer.

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.

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Cancer therapy is an emergentapplication for mRNA therapeutics. While in tumor immunotherapy, mRNA encodingfor tumor-associated antigens is delivered to antigen-presenting cells inspleen and lymph nodes, other therapeutic options benefit from immediate deliveryof mRNA nanomedicines directly to the tumor. However, tumor targeting of mRNAtherapeutics is still a challenge, since, in addition to delivery of the cargoto the tumor, specifics of the targeted cell type as well as its interplay withthe tumor microenvironment are crucial for successful intervention. This studyinvestigated lipoplex nanoparticle-mediated mRNA delivery to spheroid cellculture models of melanoma. Insights into cell-type specific targeting,non-cell-autonomous effects, and penetration capacity in tumor and stroma cellsof the mRNA lipoplex nanoparticles were obtained. It was shown that bothcoculture of different cell types as well as three-dimensional cell growthcharacteristics can modulate distribution and transfection efficiency of mRNAlipoplex formulations. The results demonstrate that three-dimensional coculturespheroids can provide a valuable surplus of information in comparison toadherent cells. Thus, they may represent in vitro models with enhancedpredictivity for the in vivo activity of cancer nanotherapeutics.

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.

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Somatic mutations in cancer cells cangenerate tumour-specific neoepitopes, which are recognized by autologous Tcells in the host. As neoepitopes are not subject to central immune toleranceand are not expressed in healthy tissues, they are attractive targets fortherapeutic cancer vaccines. Because the vast majority of cancer mutations areunique to the individual patient, harnessing the full potential of this richsource of targets requires individualized treatment approaches. Manycomputational algorithms and machine-learning tools have been developed toidentify mutations in sequence data, to prioritize those that are more likelyto be recognized by T cells and to design tailored vaccines for every patient.In this Review, we fill the gaps between the understanding of basic mechanismsof T cell recognition of neoantigens and the computational approaches fordiscovery of somatic mutations and neoantigen prediction for cancerimmunotherapy. We present a new classification of neoantigens, distinguishingbetween guarding, restrained and ignored neoantigens, based on how they conferproficient antitumour immunity in a given clinical context. Such context-baseddifferentiation will contribute to a framework that connects neoantigen biologyto the clinical setting and medical peculiarities of cancer, and will enablefuture neoantigen-based therapies to provide greater clinical benefit.

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.

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Cancer-associatedgene fusions are a potential source for highly immunogenic neoantigens, but thelack of computational tools for accurate, sensitive identification of personalgene fusions has limited their targeting in personalized cancer immunotherapy. Herewe present EasyFuse, a machine learning computational pipeline for detectingcancer-specific gene fusions in transcriptome data obtained from human cancersamples. EasyFuse predicts personal gene fusions with high precision andsensitivity, outperforming previously described tools. By testingimmunogenicity with autologous blood lymphocytes from patients with cancer, wedetected pre-established CD4+ and CD8+ T cell responses for 10 of 21 (48%) and for 1 of30 (3%) identified gene fusions, respectively. The high frequency of T cellresponses detected in patients with cancer supports the relevance of individualgene fusions as neoantigens that might be targeted in personalizedimmunotherapies, especially for tumors with low mutation burden.

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.

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Checkpoint inhibitors (CPI) haverevolutionized the treatment paradigm for advanced solid tumors; however, thereremains an opportunity to improve response rates and outcomes. In preclinicalmodels, 4-1BB costimulation synergizes with CPIs targeting the programmed celldeath protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis byactivating cytotoxic T-cell-mediated antitumor immunity. DuoBody-PD-L1×4-1BB(GEN1046) is an investigational, first-in-class bispecific immunotherapy agentdesigned to act on both pathways by combining simultaneous and complementaryPD-L1 blockade and conditional 4-1BB stimulation in one molecule. GEN1046induced T-cell proliferation, cytokine production, and antigen-specificT-cell-mediated cytotoxicity superior to clinically approved PD-(L)1 antibodiesin human T-cell cultures and exerted potent antitumor activity intransplantable mouse tumor models. In dose escalation of the ongoingfirst-in-human study in heavily pretreated patients with advanced refractorysolid tumors (NCT03917381), GEN1046 demonstrated pharmacodynamic immune effects in peripheralblood consistent with its mechanism of action, manageable safety, and earlyclinical activity [disease control rate: 65.6% (40/61)], including patientsresistant to prior PD-(L)1 immunotherapy.

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