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Article ; Online: Bispecific PD1-IL2v and anti-PD-L1 break tumor immunity resistance by enhancing stem-like tumor-reactive CD8

Tichet, Mélanie / Wullschleger, Stephan / Chryplewicz, Agnieszka / Fournier, Nadine / Marcone, Rachel / Kauzlaric, Annamaria / Homicsko, Krisztian / Deak, Laura Codarri / Umaña, Pablo / Klein, Christian / Hanahan, Douglas

Immunity

2023 Volume 56, Issue 1, Page(s) 162–179.e6

Abstract: Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most patients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects ... ...

Abstract	Immunotherapies have shown remarkable, albeit tumor-selective, therapeutic benefits in the clinic. Most patients respond transiently at best, highlighting the importance of understanding mechanisms underlying resistance. Herein, we evaluated the effects of the engineered immunocytokine PD1-IL2v in a mouse model of de novo pancreatic neuroendocrine cancer that is resistant to checkpoint and other immunotherapies. PD1-IL2v utilizes anti-PD-1 as a targeting moiety fused to an immuno-stimulatory IL-2 cytokine variant (IL2v) to precisely deliver IL2v to PD-1
MeSH term(s)	Animals ; Mice ; B7-H1 Antigen/immunology ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Disease Models, Animal ; Immunotherapy/methods ; Macrophages/immunology ; Macrophages/metabolism ; Neoplasms/therapy ; Tumor Microenvironment ; Antibodies, Bispecific/immunology ; Interleukin-2 ; Programmed Cell Death 1 Receptor/immunology
Chemical Substances	B7-H1 Antigen ; Antibodies, Bispecific ; Interleukin-2 ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2023-01-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2022.12.006
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Article ; Online: Cancer Cells Retrace a Stepwise Differentiation Program during Malignant Progression.

Saghafinia, Sadegh / Homicsko, Krisztian / Di Domenico, Annunziata / Wullschleger, Stephan / Perren, Aurel / Marinoni, Ilaria / Ciriello, Giovanni / Michael, Iacovos P / Hanahan, Douglas

Cancer discovery

2021 Volume 11, Issue 10, Page(s) 2638–2657

Abstract: Pancreatic neuroendocrine tumors (PanNET) comprise two molecular subtypes, relatively benign islet tumors (IT) and invasive, metastasis-like primary (MLP) tumors. Until now, the origin of aggressive MLP tumors has been obscure. Herein, using multi-omics ... ...

Abstract	Pancreatic neuroendocrine tumors (PanNET) comprise two molecular subtypes, relatively benign islet tumors (IT) and invasive, metastasis-like primary (MLP) tumors. Until now, the origin of aggressive MLP tumors has been obscure. Herein, using multi-omics approaches, we revealed that MLP tumors arise from IT via dedifferentiation following a reverse trajectory along the developmental pathway of islet β cells, which results in the acquisition of a progenitor-like molecular phenotype. Functionally, the miR-181cd cluster induces the IT-to-MLP transition by suppressing expression of the Meis2 transcription factor, leading to upregulation of a developmental transcription factor, Hmgb3. Notably, the IT-to-MLP transition constitutes a distinct step of tumorigenesis and is separable from the classic proliferation-associated hallmark, temporally preceding accelerated proliferation of cancer cells. Furthermore, patients with PanNET with elevated HMGB3 expression and an MLP transcriptional signature are associated with higher-grade tumors and worse survival. Overall, our results unveil a new mechanism that modulates cancer cell plasticity to enable malignant progression. SIGNIFICANCE: Dedifferentiation has long been observed as a histopathologic characteristic of many cancers, albeit inseparable from concurrent increases in cell proliferation. Herein, we demonstrate that dedifferentiation is a mechanistically and temporally separable step in the multistage tumorigenesis of pancreatic islet cells, retracing the developmental lineage of islet β cells.
MeSH term(s)	Animals ; Cell Transformation, Neoplastic ; Disease Models, Animal ; Gene Expression Regulation ; Mice ; Neuroendocrine Tumors/genetics ; Neuroendocrine Tumors/pathology ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology
Language	English
Publishing date	2021-04-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-20-1637
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Book ; Online: Biodiversity and microbial safety of artisanal Malian sour milk fènè and development of adapted starter cultures for controlled production

Wullschleger, Stephan Markus

2009

Abstract: Diss., Eidgenössische Technische Hochschule ETH Zürich, Nr. 18287, ... ...

Abstract	Diss., Eidgenössische Technische Hochschule ETH Zürich, Nr. 18287, 2009
Keywords	MILCHSÄUERUNG ; SAUERMILCHPRODUKTE UND FERMENTIERTE MILCHPRODUKTE (MILCHPRODUKTION) ; MIKROBIELLE LEBENSMITTELZUSÄTZE ; STARTER- UND SCHUTZKULTUREN (LEBENSMITTELINDUSTRIE) ; MIKROBIOLOGIE VON MILCH UND MILCHPRODUKTEN (MILCHPRODUKTION) ; LEBENSMITTEL-SICHERHEIT + LEBENSMITTEL-ÜBERWACHUNG + LEBENSMITTEL-KONTROLLE + LEBENSMITTEL-CHEMIE (ÖFFENTLICHES GESUNDHEITSWESEN) ; LEBENSMITTELHYGIENE (HUMANERNÄHRUNG) ; MALI (WESTAFRIKA). REPUBLIK MALI
Language	English
Publisher	Zürich, ETH
Publishing country	ch
Document type	Book ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The CD33xCD123xCD70 Multispecific CD3-Engaging DARPin MP0533 Induces Selective T Cell-Mediated Killing of AML Leukemic Stem Cells.

Bianchi, Matteo / Reichen, Christian / Croset, Amelie / Fischer, Stefanie / Eggenschwiler, Aline / Grübler, Yvonne / Marpakwar, Rajlakshmi / Looser, Thamar / Spitzli, Patricia / Herzog, Christel / Villemagne, Denis / Schiegg, Dieter / Abduli, Liridon / Iss, Chloé / Neculcea, Alexandra / Franchini, Marco / Lekishvili, Tamara / Ragusa, Simone / Zitt, Christof /

Kaufmann, Yvonne / Auge, Alienor / Hänggi, Martin / Ali, Waleed / Frasconi, Teresa M / Wullschleger, Stephan / Schlegel, Iris / Matzner, Mirela / Lüthi, Ursina / Schlereth, Bernd / Dawson, Keith M / Kirkin, Vladimir / Ochsenbein, Adrian F / Grimm, Sebastian / Reschke, Nina / Riether, Carsten / Steiner, Daniel / Leupin, Nicolas / Goubier, Anne

Cancer immunology research

2024

Abstract: The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized ... ...

Abstract	The prognosis of patients with acute myeloid leukemia (AML) is limited, especially for elderly or unfit patients not eligible for hematopoietic stem cell (HSC) transplantation. The disease is driven by leukemic stem cells (LSCs), which are characterized by clonal heterogeneity and resistance to conventional therapy. These cells are therefore believed to be a major cause of progression and relapse. We designed MP0533, a multispecific CD3-engaging DARPin (designed ankyrin repeat protein) that can simultaneously bind to three antigens on AML cells (CD33, CD123, and CD70), aiming to enable avidity-driven T cell-mediated killing of AML cells co-expressing at least two of the antigens. In vitro, MP0533 induced selective T cell-mediated killing of AML cell lines, as well as patient-derived AML blasts and LSCs, expressing two or more target antigens, while sparing healthy HSCs, blood, and endothelial cells. The higher selectivity also resulted in markedly lower levels of cytokine release in normal human blood compared to single antigen-targeting T-cell engagers. In xenograft AML mouse models, MP0533 induced tumor-localized T-cell activation and cytokine release, leading to complete eradication of the tumors while having no systemic adverse effects. These studies show that the multispecific-targeting strategy used with MP0533 holds promise for improved selectivity towards LSCs and efficacy against clonal heterogeneity, potentially bringing a new therapeutic option to this group of patients with high unmet need. MP0533 is currently being evaluated in a dose-escalation phase 1 study in patients with relapsed or refractory AML (NCT05673057).
Language	English
Publishing date	2024-04-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0692
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Thesis ; Online: Biodiversity and microbial safety of artisanal Malian sour milk fènè and development of adapted starter cultures for controlled production

Wullschleger, Stephan M.

2009

Keywords	MICROBIAL FOOD ADDITIVES ; PROTECTIVE AND STARTER CULTURES (FOOD INDUSTRY) ; MILCHSÄUERUNG ; SAUERMILCHPRODUKTE UND FERMENTIERTE MILCHPRODUKTE (MILCHPRODUKTION) ; LEBENSMITTEL-SICHERHEIT + LEBENSMITTEL-ÜBERWACHUNG + LEBENSMITTEL-KONTROLLE + LEBENSMITTEL-CHEMIE (ÖFFENTLICHES GESUNDHEITSWESEN) ; MIKROBIOLOGIE VON MILCH UND MILCHPRODUKTEN (MILCHPRODUKTION) ; MICROBIOLOGY OF MILK AND MILK PRODUCTS (DAIRYING) ; MILK FERMENTATION ; FERMENTED MILK PRODUCTS ; SOUR MILK PRODUCTS (DAIRYING) ; MIKROBIELLE LEBENSMITTELZUSÄTZE ; STARTER- UND SCHUTZKULTUREN (LEBENSMITTELINDUSTRIE) ; MALI (WESTERN AFRICA). REPUBLIC OF MALI ; LEBENSMITTELHYGIENE (HUMANERNÄHRUNG) ; FOOD HYGIENE + FOOD SANITATION (HUMAN NUTRITION) ; FOOD INSPECTION + FOOD CHEMISTRY + FOOD SAFETY (PUBLIC HEALTH) ; MALI (WESTAFRIKA). REPUBLIK MALI ; info:eu-repo/classification/ddc/660 ; Chemical engineering
Language	English
Publisher	ETH Zürich
Publishing country	ch
Document type	Thesis ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Book ; Online ; Thesis: Biodiversity and microbial safety of artisanal Malian sour milk fènè and development of adapted starter cultures for controlled production

Wullschleger, Stephan Markus

2009

Author's details	by Stephan Markus Wullschleger
Language	English
Size	Online-Ressource (156 S), Ill
Publisher	ETH
Publishing place	Zürich
Document type	Book ; Online ; Thesis
Thesis / German Habilitation thesis	Diss., Eidgenössische Technische Hochschule ETH Zürich, Nr. 18287--Zürich, 1828
Database	Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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Book ; Online ; Thesis: Biodiversity and microbial safety of artisanal Malian sour milk fènè and development of adapted starter cultures for controlled production

Wullschleger, Stephan Markus

2009

Author's details	by Stephan Markus Wullschleger
Language	English
Size	Online-Ressource (156 S), Ill
Publisher	ETH
Publishing place	Zürich
Document type	Book ; Online ; Thesis
Thesis / German Habilitation thesis	Diss., Eidgenössische Technische Hochschule ETH Zürich, Nr. 18287--Zürich, 1828
Database	Former special subject collection: coastal and deep sea fishing

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Article: Vagococcus teuberi sp. nov., isolated from the Malian artisanal sour milk fènè

Wullschleger, Stephan / Christoph Jans / Clelia Seifert / Sarah Baumgartner / Christophe Lacroix / Bassirou Bonfoh / Marc J.A. Stevens / Leo Meile

Systematic and applied microbiology. 2018 Mar., v. 41, no. 2

2018

Abstract: Ten bacterial isolates belonging to the genus Vagococcus were obtained from Malian sour milk fènè produced from spontaneously fermented cow milk. However, these isolates could not be assigned to a species upon initial comparative 16S rRNA gene sequence ... ...

Abstract	Ten bacterial isolates belonging to the genus Vagococcus were obtained from Malian sour milk fènè produced from spontaneously fermented cow milk. However, these isolates could not be assigned to a species upon initial comparative 16S rRNA gene sequence analysis and were therefore further characterized. Rep-PCR fingerprinting of the isolates yielded four strain clusters represented by strains CG-21T (=DSM 21459T), 24CA, CM21 and 9H. Sequence identity of the 16S rRNA gene of DSM 21459T to its closest relative species Vagococcus penaei was 97.9%. Among the four rep strain clusters, DSM 21459T and 24CA shared highest 16S rRNA gene sequence identity of 99.6% while CM21 and 9H shared 98.6–98.8% with DSM 21459T and V. penaei CD276T. DSM 21459T and 24CA were thus subjected to a polyphasic typing approach. The genome of DSM 21459T featured a G+C content of 34.1mol% for a 2.17-bp chromosome and a 15-kbp plasmid. Average nucleotide identity (ANI) of DSM 21459T to Vagococcus fluvialis bH819, V. penaei CD276T were 72.88%, 72.63%, respectively. DNA–DNA hybridization (DDH) similarities of strain DSM 21459T to other Vagococcus species were <42.0%. ANI and DDH findings strongly supported the 16S rRNA gene phylogenetic tree delineations. The fatty acid patterns of DSM 21459T was palmitic acid (C 16:0, 24.5%), oleic acid (C 18:1-ω9c, 32.8%), stearic acid (C 18:0, 18.9%). General physiological characterization of DSM 21459T and 24CA were consistent with those of the genus Vagococcus. Strain DSM 21459T and further strains are therefore considered to belong to a novel species, for which the nomenclature Vagococcus teuberi sp. nov. is proposed. The type strain is named CG-21T (=DSM 21459T and LMG 24695T).
Keywords	Vagococcus fluvialis ; chromosomes ; genes ; nucleic acid hybridization ; nucleotide sequences ; oleic acid ; palmitic acid ; phylogeny ; plasmids ; polymerase chain reaction ; ribosomal DNA ; ribosomal RNA ; sequence analysis ; sour milk ; stearic acid ; traditional technology
Language	English
Dates of publication	2018-03
Size	p. 65-72.
Publishing place	Elsevier GmbH
Document type	Article
ZDB-ID	283612-9
ISSN	1618-0984 ; 0723-2020
ISSN (online)	1618-0984
ISSN	0723-2020
DOI	10.1016/j.syapm.2017.11.003
Database	NAL-Catalogue (AGRICOLA)

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Ud II Zs.7: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.A 6291: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Nanoparticle Conjugation of Human Papillomavirus 16 E7-long Peptides Enhances Therapeutic Vaccine Efficacy against Solid Tumors in Mice.

Galliverti, Gabriele / Tichet, Mélanie / Domingos-Pereira, Sonia / Hauert, Sylvie / Nardelli-Haefliger, Denise / Swartz, Melody A / Hanahan, Douglas / Wullschleger, Stephan

Cancer immunology research

2018 Volume 6, Issue 11, Page(s) 1301–1313

Abstract: Treatment of patients bearing human papillomavirus (HPV)-related cancers with synthetic long-peptide (SLP) therapeutic vaccines has shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas ... ...

Abstract	Treatment of patients bearing human papillomavirus (HPV)-related cancers with synthetic long-peptide (SLP) therapeutic vaccines has shown promising results in clinical trials against premalignant lesions, whereas responses against later stage carcinomas have remained elusive. We show that conjugation of a well-documented HPV-E7 SLP to ultra-small polymeric nanoparticles (NP) enhances the antitumor efficacy of therapeutic vaccination in different mouse models of HPV
MeSH term(s)	Animals ; Antibodies/pharmacology ; CD8-Positive T-Lymphocytes/immunology ; Cancer Vaccines/chemistry ; Cancer Vaccines/immunology ; Cancer Vaccines/pharmacology ; Female ; Lung Neoplasms/secondary ; Mice, Inbred C57BL ; Mice, Transgenic ; Nanoparticles/chemistry ; Neoplasm Recurrence, Local ; Neoplasms, Experimental/immunology ; Neoplasms, Experimental/mortality ; Neoplasms, Experimental/therapy ; Papillomavirus E7 Proteins/chemistry ; Papillomavirus E7 Proteins/immunology ; Papillomavirus E7 Proteins/pharmacology ; T-Lymphocytes, Regulatory/immunology ; Treatment Outcome ; Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology ; Vaginal Neoplasms/immunology ; Vaginal Neoplasms/pathology ; Vaginal Neoplasms/prevention & control
Chemical Substances	Antibodies ; Cancer Vaccines ; Papillomavirus E7 Proteins ; Tumor Necrosis Factor Receptor Superfamily, Member 9 ; oncogene protein E7, Human papillomavirus type 16
Language	English
Publishing date	2018-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-18-0166
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Article ; Online: Quantitative MRI establishes the efficacy of PI3K inhibitor (GDC-0941) multi-treatments in PTEN-deficient mice lymphoma.

Wullschleger, Stephan / García-Martínez, Juan M / Duce, Suzanne L

Anticancer research

2012 Volume 32, Issue 2, Page(s) 415–420

Abstract: Aim: To assess the efficacy of multiple treatment of phosphatidylinositol-3-kinase (PI3K) inhibitor on autochthonous tumours in phosphatase and tensin homologue (Pten)-deficient genetically engineered mouse cancer models using a longitudinal magnetic ... ...

Abstract	Aim: To assess the efficacy of multiple treatment of phosphatidylinositol-3-kinase (PI3K) inhibitor on autochthonous tumours in phosphatase and tensin homologue (Pten)-deficient genetically engineered mouse cancer models using a longitudinal magnetic resonance imaging (MRI) protocol. Materials and methods: Using 3D MRI, B-cell follicular lymphoma growth was quantified in a Pten(+/-)Lkb1(+/hypo) mouse line, before, during and after repeated treatments with a PI3K inhibitor GDC-0941 (75 mg/kg). Results: Mean pre-treatment linear tumour growth rate was 16.5±12.8 mm(3)/week. Repeated 28-day GDC-0941 administration, with 21 days 'off-treatment', induced average tumour regression of 41±7%. Upon cessation of the second treatment (which was not permanently cytocidal), tumours re-grew with an average linear growth rate of 40.1±15.5 mm(3)/week. There was no evidence of chemoresistance. Conclusion: This protocol can accommodate complex dosing schedules, as well as combine different cancer therapies. It reduces biological variability problems and resulted in a 10-fold reduction in mouse numbers compared with terminal assessment methods. It is ideal for preclinical efficacy studies and for phenotyping molecularly characterized mouse models when investigating gene function.
MeSH term(s)	Animals ; Cell Line, Tumor ; Disease Models, Animal ; Enzyme Inhibitors/pharmacology ; Female ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/enzymology ; Head and Neck Neoplasms/pathology ; Indazoles/pharmacology ; Longitudinal Studies ; Lymphoma, B-Cell/drug therapy ; Lymphoma, B-Cell/enzymology ; Lymphoma, B-Cell/pathology ; Lymphoma, Follicular/drug therapy ; Lymphoma, Follicular/enzymology ; Lymphoma, Follicular/pathology ; Magnetic Resonance Imaging/methods ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; PTEN Phosphohydrolase/deficiency ; Phosphoinositide-3 Kinase Inhibitors ; Sulfonamides/pharmacology
Chemical Substances	2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine ; Enzyme Inhibitors ; Indazoles ; Phosphoinositide-3 Kinase Inhibitors ; Sulfonamides ; PTEN Phosphohydrolase (EC 3.1.3.67) ; Pten protein, mouse (EC 3.1.3.67)
Language	English
Publishing date	2012-01-27
Publishing country	Greece
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
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