Events and Seminars

Immunology Day 20 June 2024

@GCIR_Villa Fondation Jeantet

Scheduled for June 20th, this event will gather researchers from both Geneva and the Arche Lémanique regions who share an interest in various facets of immunology, spanning inflammation, infection, and cancer. The symposium agenda will feature alternating presentations from pharmaceutical sector representatives and esteemed researchers from UNIGE and HUG. This collaborative effort is being organised by the University of Geneva and Light Chain Bioscience. We are particularly honoured to announce that our keynote speaker will be Professor George Coukos from Ludwig Cancer Research, Lausanne.

Scroll down to read the abstracts!

 

Thursday, June 20, 2024

9:00 am to 6:00 pm

IMMUNOLOGY DAY 2024 | PROGRAMME

Louis Jeantet Auditorium

Route de Florissant 77 CH-1206 Geneva

 

8:45 Welcome Coffee

 

9:15 Welcome, Stéphanie HUGUES (UNIGE)

Chair: Alain VICARI (Managing Director, Calypso Biotech – a Novartis Company)

09:20 Paul BRADFIELD - CEO, Co-founder - MesenFlow Technologies
Multi-throughtput vascularized organoids: Developing a bio-imaging platform for studying leukocyte trafficking under flow

09:40 Paula NUNES-HASLER – PI - Dept of Pathology and Immunology – UNIGE Faculty of Medicine
Exploring and Improving Dendritic Cell Antigen Cross-Presentation

10:00 Liqing CHENG – Post-doc – Dept of Pathology and Immunology – UNIGE Faculty of Medicine
Local antigen encounter promotes generation of tissue-resident memory T cells in the large intestine (Becattini lab)

10:20 Benjamin MEYER – PI - Dept of Pathology and Immunology – UNIGE Faculty of Medicine
Mucosal Immunity: the key to reduce SARS-CoV-2 transmission?

 

10:40 - 11:10 Coffee Break

 

Chair: Christoph SCHEIERMANN (UNIGE)

11:10 Ian MCGOWAN - Chief Medical Officer - Orion Biotechnology
Unlocking GPCRs for inflammatory diseases and immuno-oncology

11:30 Arnaud HUARD – Post-doc – Dept of Pathology and Immunology – UNIGE Faculty of Medicine
Role of inflammasomes in the CpG-induced macrophage activation syndrome (Gabay lab)

11:50 Emma FIORINI - Senior Expert Research – Ac Immune
Advantages of next generation SupraAntigen® liposomal vaccine platform to immunize against pathological targets of Alzheimer’s disease (AD)

12:10 Maria SHUTOVA – Post-doc – Dept of Pathology and Immunology – UNIGE Faculty of Medicine
Mechanoregulation of TGFβ signalling in skin inflammation (Boehnke lab)

 

12:30 – 14:00 Lunch

 

14:00 George COUKOS – MD, Director of the Department of Oncology- CHUV and University of Lausanne, and the Ludwig Cancer Research Lausanne Branch
Keynote speaker: Understanding and optimising TIL adoptive therapy for solid tumours

Chair: Camilla JANDUS (UNIGE)

14:50 Julien MONTORFANI - PhD student - Light Chain Bioscience
A tumour-selective IL-2R/IL-15R agonistic bispecific antibody combination reduces tumor burden and systemic toxicity

15:10 Beatrice ZITTI– Post-doc – Dept of Pathology and Immunology – UNIGE Faculty of Medicine
Immune regulation of CCR7+ dendritic cells at tumor sites.

15:30 Erika RIVA – Senior scientist – AMAL Therapeutics
Bimodal effect of NKG2A blockade on intratumoral and systemic CD8 T cell response induced by cancer vaccine

15:50 Flavia FICO – Post-doc – Dept of Pathology and Immunology – UNIGE Faculty of Medicine
Harnessing immune cell infiltration in breast cancer for improved immunotherapy (Hugues lab)

 

16:10 – 16:40 coffee break

 

Chair: Nicolas FISCHER (CEO, Light Chain Bioscience)

16:40 Sara MAJOCCHI - Discovery project leader - Light Chain Bioscience
CD28 bispecific antibodies mediating conditional costimulation of T cells for enhanced tumour control.

17:00 Mahdia BENKHOUCHA – Post-doc – Dept of Pathology and Immunology – UNIGE Faculty of Medicine
Study of the HGF/c-Met pathway in T cells during neuroinflammation (in mice and humans) (Lalive Lab)

17:20 Carmen PICON - Post-doc – Dept of Pathology and Immunology – UNIGE Faculty of Medicine
Neuronal epigenetic remodeling sustains cortical pathology in Multiple Sclerosis (Merkler lab)

17:40 Mario PERRO - SVP, Head of Biologics Research & Site Head - Ichnos Glenmark Innovation
ISB 2001, a BCMA and CD38 dual targeting T cell engager, demonstrates superior cytotoxicity relative to teclistamab in the samples of patients relapsing from CD38 and BCMA targeted immunotherapies

18:00 - Conclusion, Walter FERLIN (CSO, Light Chain Bioscience)

 

18:10 - Closing apéro


Event organized by the Department of Pathology and Immunology, the Geneva Centre for Inflammation Research (both at the Faculty of Medicine, University of Geneva), and Light Chain Bioscience.

 

MANY THANKS TO THE EVENT'S SPONSORS!

 

ABSTRACTS

 

Paul BRADFIELD

MesenFlow has established a microscopy platform for testing inflammatory pathologies using human vascular endothelial cells imitating blood vessels under flow and circulating human immune cells. In partnership with Professor Roux, MesenFlow is now developing more complex systems using an organ-on-a-chip format. These include a second tissue organoid culture chamber where direct contact with the vascular compartment can further augment their behaviour leading to increased capture, migration and transmigration of leukocytes under flow. This novel microphysiological system is being validated using a blood-brain-barrier model, where AI algorithms developed by MesenFlow to measure leukocyte trafficking events in real-time are also being evaluated.  

 

Paula NUNES-HASLER

The activation of CD8+ cytotoxic T lymphocytes by dendritic cells (DCs) through antigen cross-presentation is a process central to adaptive immunity against intracellular pathogens and cancer cells. Stimulating this can help improve effectiveness of vaccines or anti-cancer immunotherapies aiming to stimulate CD8 T cell proliferation and activity.  Cross-presentation is more efficient when antigens are acquired through phagocytosis, and it requires an intimate communication between the phagosome and the endoplasmic reticulum (ER), yet molecular details of how phagocytosis and the ER help to shape T cell responses is still poorly understood. Previously, our work uncovered mechanisms of ER-mediated lipid and calcium signaling that influence phagosome maturation and antigen processing. More recently, we’ve leverage this knowledge to perform a targeted screen, identifying new compounds that improve cross-presentation in vitro in both mouse and human DCs. Importantly, we found two compounds that improve the therapeutic effect of an anti-melanoma DC-vaccine immunotherapy model, improving both numbers and qualities of CD4 and CD8 T cell recruitment to tumours and reducing tumour growth. Our ongoing studies suggest these effects are primarily due to changes in secreted factors rather than direct effects on antigen processing. These findings underscore the potential of targeting ER-mediated pathways to enhance the efficacy of DC-based immunotherapies for treating cancer and infectious diseases. 

 

Liqing CHENG

Upon infection, primed CD8+ T cells migrate to the invaded tissue, where they differentiation into tissue-resident memory cells (Trm). Despite the importance of these cells, our understanding of their molecular landscape and the signals that dictate their development remains limited, particularly in large intestine (LI). Here, we report that cognate antigen recognition as a major driver of Trm differentiation at this anatomical site, which not only promotes the proliferation of effector cells but also facilitates the acquisition of transcriptional features. Thus, antigen recognition in the LI favors the establishment of Trm by impacting T cell expansion and gene expression.

 

Benjamin MEYER

Mucosal antibodies are pivotal for the protection against SARS-CoV-2 infection in the upper respiratory tract, potentially limiting virus replication and transmission. Our understanding of mucosal immunity to SARS-CoV-2, however, remains limited.

In this study, we analyzed SARS-CoV-2 mucosal antibodies following previous infection, vaccination, or a combination of both and examined the relationship between pre-existing mucosal antibodies and infectious viral shedding. We demonstrate that SARS-CoV-2 infection generates higher titers of binding and neutralizing mucosal antibodies compared to vaccination alone. Such potent responses reduce viral shedding. Our results support the need to develop SARS-CoV-2 vaccines that elicit mucosal antibodies.

 

Ian MCGOWAN

Orion Biotechnology is a clinical stage company founded in 2017, with established R&D operations in Geneva, Switzerland and headquarters in Ottawa, Canada. Orion is leveraging its proprietary PROcisionXTM platform to offer one of the fastest drug discovery solutions in industry (3-6 month from target identification to preclinical leads). Orion´s drugs are small protein analogues of naturally occurring GPCR ligands. Our technology can target more than 90 valuable class A and class B GPCRs implicated in immunological, oncological, and cardiometabolic diseases.

 

Arnaud HUARD

Macrophage activation syndrome (MAS) is a life-threatening inflammatory condition. Elevated circulating levels of IL-18 are assumed to be pathogenic. IL-18 is initially produced as a pro-peptide, cleaved by caspase-1 upon inflammasome activation and naturally inhibited by IL-18 binding protein (IL-18BP) upon formation of high affinity complexes. While the phenotype of Casp1-/- and Gsmd-/- did not differ from their WT littermates, we observed that the severity of MAS was markedly attenuated in Il18bp-/-Casp1-/- and Il18bp-/-Gsmd-/- compared to Il18bp-/- littermates, including decreased body weight loss and splenomegaly. The severity of CpG-induced MAS in Il18bp-/- mice is dependent IL-18 maturation by caspase-1 and released by gasdermin-D.

 

Emma FIORINI

Aggregated forms of amyloid beta (Abeta) and phosphorylated (p)Tau are the main components of neurotoxic Abeta plaques and neurofibrillary tangles present in brains of Alzheimer’s disease patients. We target both Abeta and Tau with our liposome-based SupraAntigen® vaccine technology. Non-human primates immunized with Abeta vaccine develop a robust and boostable antibody titers over time, which engaged relevant pathological species, such as Abeta oligomers and pyroglutamate-Abeta. For Tau, only the liposome-based SupraAntigen® vaccine matured a repertoire of antibodies that broadly recognized species containing the pathological pTau. Taken together, the SupraAntigen® vaccine technology platform creates a broad antibody response to the key pathological species.

 

Maria SHUTOVA

TGFβ is a key regulator of skin homeostasis. TGFβ1 isoform is implicated in psoriasis pathogenesis; however, the isoform-specific regulation of TGFβ signaling is not well understood. We explore the mechanisms specific for the activation of latent TGFβ1 using clinical data, 3D human skin models, cytokine induction models of psoriatic inflammation and mechanobiological approaches to synthetic morphogenesis.

We show that the inflammatory stimuli promote the expression and activation of TGFβ-activating αvβ6 integrin via mechanodependent mechanism. Our data indicate that inflammation drives synergistic changes in the epidermis contributing to mechanodependent positive feedback loop to upregulate the TGFβ1 signaling in the skin.

 

Julien MONTORFANI

Severe systemic toxicities have limited the use of immune-stimulating cytokines as cancer immunotherapies. To harness the benefits of cytokine stimulation and avoid the associated systemic toxicities, we describe here a combination of two bispecific antibodies (bsAbs). We use bsAbs that target the dimeric IL-2/IL-15 receptor (composed of CD122 and CD132) and a tumor associated antigen to activate immune cells in a tumor restricted manner. This approach may be applicable to other cytokines that were previously avoided in immunotherapies because of their associated toxicities.

 

Beatrice ZITTI

Immune infiltrates in the tumor microenvironment (TME) vary across patients and can influence immunotherapy outcomes. Previous studies have shown that there is a finite number of dendritic cell (DC) states infiltrating solid tumors which are conserved across different cancer types. Expression of CCR7 marks DC that also reside at tumor sites and have been associated with better survival for cancer patients and response to immune checkpoint blockade (ICB) therapy. Considering that CCR7+ DC have been described to also express immunoregulatory genes, we analysed potential mechanisms of suppression of these cells that could be important to restrict anti-tumor immunity.

 

Erika RIVA

Therapeutic heterologous prime-boost vaccination with KISIMATM protein vaccine and VSV-GP-TAg oncolytic virus was shown to inflame the tumor microenvironment promoting significant infiltration of antigen-specific CD8 T cells resulting in robust antitumoral efficacy in mouse tumor models. Here, we report the impact of NKG2A blockade on antitumoral CD8 T cell immune response elicited by KISIMA – VSV-GP-TAg vaccination. Combination therapy significantly reduced the amount of vaccine-induced exhausted CD8 T cells infiltrating the tumor whereas influenced the establishment of systemic effector memory CD8 T cell response showing a compartment-dependent effect of NKG2A blockade on cancer vaccine-induced T cell immunity.

 

Flavia FICO

Due to the growing interest in cancer-associated fibroblasts (CAFs) targeting and reprogramming, it is worth investigating whether their presence in the tumor microenvironment could improve immunotherapy. By using EO771 tumor-bearing mice we identified a subpopulation of CAFs expressing CCL19 which seem to orchestrate adaptive immune responses upon anti-PD-1 administration. We also integrate bioinformatic analysis of public data bases for established signatures and perform high dimensional analysis of FACS-sorted CAFs in human breast cancer samples by scRNASeq. We aim at developing new therapeutic strategies to enhance the efficacy of immunotherapy in poorly responsive tumors.

 

Sara MAJOCCHI

By associating a blocking anti-PD-L1 antibody arm with an agonist anti-CD28 antibody arm, we generated a PD-L1xCD28 bsAb (NI-3201) inducing CD28 signaling upon PD-L1 blockade on PD-L1+ tumor and immune cells (e.g., antigen-presenting cells). Data from the preclinical development of NI-3201 will be presented, with a focus on in vitro and in vivo de-risking activities.

 

Mahdia BENKHOUCHA

c-Met, a tyrosine kinase receptor, is the unique receptor for hepatocyte growth factor (HGF). The HGF/c-Met axis is reported to modulate cell migration, maturation, cytokine production, and antigen presentation. Here, we report that CD4+c-Met+ T cells are detected at increased levels in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS). CD4+c-Met+ T cells found in the CNS during EAE peak disease are characterized by a pro-inflammatory phenotype skewed towards a Th1 and Th17 polarization, with enhanced adhesion and transmigration capacities correlating with increased expression of integrin α4 (Itgα4). We also analyzed c-Met expression on human CD4 T cells from multiple sclerosis (MS) patients versus patients with non-inflammatory neurological disease (NIND), with the goal to better understand the role of this T cell sub-population in MS disease. PBMCs were isolated from blood and cerebrospinal fluid (CSF) samples of MS and NIND patients from December 2020 to December 2022 at the Geneva University Hospital. Phenotypic and functional characterization was in part by determined by flow cytometry (paired blood and CSF) and bulk RNA sequencing (blood). Adhesion and transmigration capacities were studied to further characterize the function of c-Met+ CD4 T cells. c-Met+ non-naïve CD4 T cells were detected at higher levels in both blood.

These results highlight c-Met as an immune marker of highly pathogenic pro-inflammatory and pro-migratory CD4+ T lymphocytes associated with neuroinflammation.

 

Carmen PICON

In Multiple Sclerosis (MS) the accumulation of nerve cell damage, known as neurodegeneration, stands as a primary driver of irreversible neurological disability and cognitive dysfunction. This damage is often intertwined with the presence of inflammatory mediators in the brain milieu. Despite this understanding, the specific impact of the inflammatory environment on neuronal function, particularly its effect on the epigenetic and transcriptomic landscape, remains unexplored. We conducted a neuropathological examination on post-mortem frozen tissues from 29 progressive MS cases and 18 non-neurological controls. Subsequently, we isolated neuronal Fluorescence-Activated Nuclear Sorting (FANS) and analysed their DNA methylation profile using the Infinium Methylation EPIC array. Our findings reveal significant alterations in the methylome on neurons. Remarkably, inhibitory neurons displayed specific differential methylated positions), with a notable loss of methylation in genes associated to neuroinflammation. Conversely, hypermethylated DMP were associated with genes involved in neuronal function suggesting an interplay between increased inflammation with reduced neuronal activity. Excitatory neurons did not show methylation remodelling. These results provide the first evidence of an epigenetic remodelling event in inhibitory neurons in Multiple Sclerosis and offer insights into potential molecular targets for therapeutic intervention.

 

Mario PERRO

Title: ISB 2001, a BCMA and CD38 dual targeting T Cell Engager, demonstrates superior cytotoxicity relative to teclistamab in the samples of patient relapsing from CD38 and BCMA targeted immunotherapies.

Abstract

Immunotherapies targeting single tumor associated antigens (TAA) demonstrated efficacy against multiple myeloma (MM). However, durable responses are still limited1 potentially due to expansion of clones with low target expression2

We demonstrate that simultaneous targeting of BCMA and CD38 on MM tumor cells with heterogenous expression of these antigens using dual targeting ISB 2001, enables superior killing relative to mono-targeting T cell engagers (TCE) 3.

In relapsed/refractory (r/r) patients, which received CD38 targeted therapy, daratumumab cytotoxicity was substantially reduced due to low CD38 expression. Teclistamab is considered the next line of treatment in such patients. However, ISB 2001 consistently demonstrated increased cytotoxicity compared to teclistamab in both newly diagnosed patient and r/r patient samples.

ISB 2001 was also more potent compared to the combination of teclistamab and daratumumab in cytotoxic assay using healthy donors. ISB 2001 showed superiority to both teclistamab and daratumumab as single agents, as well as when they were used in combination.

Additionally, ISB 2001 was compared against a combination of daratumumab and teclistamab in a humanized mouse model of multiple myeloma with a low expression of both CD38 and BCMA, mimicking potential tumour escape expanding clones. ISB 2001 induced complete eradication of the tumors in almost all animals whereas the combination only showed partial tumor protection, again suggesting that dual targeting by TCE is superior to two therapeutic agents individually targeting the same antigens.

In conclusion, ISB 2001 showed superiority to both daratumumab and teclistamab in preclinical models.

 

Munshi, N. C. et al. 384, 705–716 (2021).

Nijhof, I. S. et al. Blood 128, 12 (2016).

(https://doi.org/10.1182/blood-2022-159353)

 

 

 

24 May 2024

Events and Seminars