Alsya Affandi: NWO Veni award for nanovaccine and dendritic cells research

Alsya Affandi receives the prestigious Veni grant of 280,000 euros from The Dutch Research Council NWO, for his research in developing nanovaccines for treatment of cancer and autoimmunity.

Our immune system is key for protection against pathogens and malignant cells. Impairment of the immune system can lead to failure to clear viral or bacterial infection, or to prevent tumor development. On the other hand, uncontrolled immune responses can also lead to the development of chronic autoimmune diseases. Dendritic cells (DCs) are the master regulators of immune system with tremendous immunotherapy potential, however current DC-based therapies are still lacking effectiveness in treating these diseases.

To overcome this challenge, Alsya Affandi’s research proposal “Nanotrivax: three-component nanobody-vaccines targeting human dendritic cells for immunotherapy” aims to use nanobodies to deliver vaccine components specifically towards DCs. This approach is expected to be more effective in activating T cells to eliminate cancer cells, or in promoting regulatory T cells to dampen chronic inflammation. This will allow us to harness DCs to improve current immunotherapies in cancer and autoimmunity.

The NWO talent programme awards the Veni funding to highly promising young scientists who have recently obtained their PhDs that will enable them to develop their own ideas in the period of three years. From the ENW and ZonMW domains, 89 researchers have been awarded these grants, in which Alsya Affandi is among the four laureates from Amsterdam UMC.

 

 

Febe van Maldegem

About

Febe van Maldegem is group leader in the Department of Molecular Cell Biology & Immunology. Her work focusses on the complex role of the tumour microenvironment in non-small cell lung cancer (NSCLC), crucial for mediating anti-tumour immunity, but more frequently imposing resistance to therapy. Key to her work is the use of highly multiplex technologies, such as Imaging Mass Cytometry with which the tumour microenvironment can be studied in great detail, revealing the activation states as well as the spatial context of the many cells within the tissue. Febe van Maldegem’s research program, supported by award of the Amsterdam UMC fellowship, aims to improve therapeutic options for patients with non-small cell lung cancer by rationalising the design of combination, mindful of the important role for the tumour microenvironment in determining success.

Research Lines

The NSCLC TME as biomarker and therapeutic target

In order to understand how we can manipulate the TME to benefit therapeutic strategies, we will first need to better understand the dynamics within this complex system. This research line asks the basic questions: How does the TME evolve over time during tumour development, and what are the selective forces that drive this evolution? In several in vivo models for non-small cell lung cancer we study the changes in TME composition, at early time points from tumour onset into advanced tumour stages and under different experimental conditions. Imaging Mass Cytometry will provide detailed phenotypic and spatial characterisation of the cellular relationships in the tissue. The resulting spatial TME profiles will be used to generate biomarkers for response to therapy and to design novel therapeutic targets aimed at disrupting or enhancing cellular interactions. 

Video, sequentially highlighting 15 out of the 27 markers this small lung tumour was stained for using Imaging Mass Cytometry (CX3CR1, PECAM, aSMA, EPCAM, B220, CD103, LY6G, CD8, CD4, CD11c, CD68, F480, CD45, CD44, MHC-II)

Rationally combining chemoradiotherapy with immune checkpoint inhibitors (ICI)

Neoadjuvant (chemo)radiotherapy (CRT) is the current  standard of care for low grade NSCLC, but the field is moving towards combinations with ICI. Chemotherapy and radiotherapy can benefit immune responses by inducing immunogenic cell death, but can also be toxic to the immune cells. We will assess the impact of this treatment combination by analysing patient samples from current clinical trials, comparing different combinations of these therapies in pre- and post-treatment biopsies. In vitro and pre-clinical studies will be used to optimise the treatment dosing and scheduling, to provide a rational basis for design of the next generation of clinical trials.  

Key publications

Mugarza E, van Maldegem F, Boumelha J, Moore C, Rana S, Sopena ML, East P, Ambler R, Anastasiou P, Clavijo PR, Valand K, Cole M, Molina-Arcas M, Downward J. Therapeutic KRASG12C inhibition drives effective interferon-mediated anti-tumour immunity in immunogenic lung cancers. Preprint in bioRxiv, October 19, 2021.  doi: 10.1101/2021.10.18.464819, Submitted for publication.

 

Van Maldegem F, Valand K, Cole M, Patel H, Angelova M, Rana S, Colliver E, Enfield K, Bah N, Tsang VSK, Mugarza E, Moore C, Hobson P, Levi D, Molina-Arcas M, Swanton C, Downward J. Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry. Nature Communications. 2021 Oct 8;12. doi: 10.1038/s41467-021-26214-x

 

van Maldegem F, Downward J. Mutant KRAS at the Heart of Tumor Immune Evasion. Immunity. 2020 Jan 14;52(1):14-16. doi: 10.1016/j.immuni.2019.12.013

 

Molina-Arcas M, Moore C, Rana S, van Maldegem F, Mugarza E, Romero-Clavijo P, Herbert E, Horswell S, Li LS, Janes MR, Hancock DC, Downward J. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019 Sep 18;11(510):eaaw7999. doi: 10.1126/scitranslmed.aaw7999

 

van Maldegem F, Maslen S, Johnson CM, Chandra A, Ganesh K, Skehel M, Rada C. CTNNBL1 facilitates the association of CWC15 with CDC5L and is required to maintain the abundance of the Prp19 spliceosomal complex. Nucleic Acids Res. 2015 Aug 18;43(14):7058-69. doi: 10.1093/nar/gkv643

 

Group members

Other PI's

Gijs Kooij: Pro-resolving lipid mediator Lipoxin A4 reduces neuro-inflammation in MS models

A research group of the multiple sclerosis (MS) Center Amsterdam, led by assistant professor Gijs Kooij, studied the clinical potential of pro-resolving lipid mediator Lipoxin A4 in MS and model systems. They discovered that this lipid mediator not only ameliorated neuro-inflammation, but also that it dampened pro-inflammatory T cell responses in MS patient-derived cells. These results are now published in Cell Reports.

NWO Subsidy for innovative research into mini-brains

 Elly Hol of UMC Utrecht Brain Center and Elga de Vries of Amsterdam UMC receive 1.3 million euro subsidy from NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) for their innovative research into mini-brains!

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The development of drugs for brain diseases is difficult for several reasons. Unfortunately, the blood-brain barrier, which is there to prevent all kinds of undesirable substances from entering the brain, also causes important medicines to be stopped. In addition, animal models with which research is carried out mimic but limit the disease in patients.
 
The research by Elly Hol and Elga de Vries, called CONNECT, aims to develop a human cell model that is closer to the patient than current cell and animal models. They do this by using the latest technology from human stem cells to develop blood-brain barrier cells and link them to mini-brains.

More about the granting of a total of 5 million euros for research into human measurement models on the 
NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) website : https://lnkd.in/d-5A8gC

Sanne Verberk – publication in Frontiers in Immunology on the role of macrophage ACLY in regulating inflammatory responses and disease outcomes

Our second paper on ATP citrate lyase (Acly) is published in Frontiers in Immunology!

In our previous paper we showed beneficial effects of targeting macrophage-specific Acly in the context of atherosclerosis. Here, we showed that despite a marked regulation of inflammatory responses in vitro, macrophage Acly deficiency does not translate into huge alterations in other acute and chronic inflammatory disorders in vivo.

Lynn van Olst – Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

Multiple sclerosis (MS) is the most common chronic neurodegenerative and neuroinflammatory disease in young adults and despite availability of many disease-modifying therapies most patients will eventually develop secondary progressive MS. Here, we uncovered two distinct MS-specific phenotypes of brain resident immune cells, microglia, that are driven by local meningeal inflammation and differentially associate with neuronal damage. Results suggest that these phenotypes may occur sequentially during chronic meningeal inflammation and that microglia lose their protective properties over time, leading to neuronal loss. Hence, timely targeting of the processes contributing to microglial activation in the progressive MS cortex provides an interesting therapeutic strategy to combat progressive MS.

 

 

The management of the MS Center Amsterdam will change as of April, 2021

In addition to general director professor Bernard Uitdehaag, professor Elga de Vries will join the newly established executive board as scientific director. Besides the two directors senior researchers from seven different departments where MS research is performed will form the general board of the MS Center Amsterdam.

 

Managing board

Professor Bernard Uitdehaag, neurologist and chair of the department of Neurology at Amsterdam UMC, has been director of MS Center Amsterdam since 2013. From April 1, he will be joined for the daily management by professor Elga de Vries. She has been at Amsterdam UMC since 2000 as a neuro-immunological researcher in the department of Molecular Cell Biology and Immunology. Her research group Neuro-immunology focuses on unraveling disease mechanisms of MS at a cellular level in order to find new targets for treatments.

 

General Board

The general board consists of eight senior researchers from seven departments within Amsterdam UMC. Their task is to jointly provide the vision and mission of the MS Center Amsterdam and a draw a strategy to achieve set goals.

 

Members general board

·         prof. dr. Jeroen Geurts, Anatomy and Neuroscience

·         prof. dr. Vincent de Groot, Rehabilitation medicine

·         prof. dr. Joep Killestein, Neurology

·         prof. dr. Charlotte Teunissen, Clinical chemistry

·         prof. dr. Bernard Uitdehaag, Neurology

·         prof. dr. Paul van der Valk, Pathology

·         dr. ir. Hugo Vrenken, Radiology and nuclear medicine

·         prof. dr. Elga de Vries, Molecular Cell Biology and Immunology

 

MS Center Amsterdam Office

The managing and general board will be supported by the MS Center Amsterdam Office.

·         dr. Annette van der Goes

·         Karin Husken

 

Ernesto Rodriguez Camejo – publication in Nature Communications: Sialic acids in pancreatic cancer cells drive tumour-associated macrophage differentiation via the Siglec receptors Siglec-7 and Siglec-9

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most severe cancer types with a

5-year survival of 9% . The PDAC TME is characterized by dense fibrotic stroma
and suppressive immune cells that repress anti-tumor immune responses and
contribute to cancer progression. In this paper, Rodriguez et al showed that
pancreatic tumor cells present an increased expression of a particular glycan
structure, sialic acid, capable to shape immune responses by inducing
tolerogenic programs in myeloid cells. This work highlights a critical role for
sialylated glycans in controlling immune suppression and provides new potential
targets for cancer immunotherapy in PDAC.