IMMUUN€¦ · IMMUUN for every professional in the immunology chain Linde Meyaard The delicate balance between activation and inhibition Amsterdam hosts European Congress of Immunology

IMMUUNfor every professional in the immunology chain

Linde Meyaard

The delicate balance

between activation

and inhibition

Amsterdam hosts

European Congress

of Immunology 2021

Sepsis from

droplet to

diagnosis

Volume 4 - Issue 2 - October 2015 -

Paul-Peter TakFocus on disease mechanisms

Theme cross-disease immunology Building Bridges

dominique BaetenPredicT success oF

TargeTed TheraPy

3October 2015 IMMUUN

contentsCOLOPHON

Immuun is published by the NVVI and written and edited by Bureau Lorient Communicatie BV. In 2015, Immuun will have three issues. The target groups are NVVI members, relevant clinicians, suppliers and other partners of immunologists as well as policy makers.

EDITORIAL BOARDdr. godelieve de BreeProf.dr. mieke Bootsdr. hans Jacobsdr. edward KnolProf.dr. yvette van Kooyk (chair)dr. andrea Woltman

REcOmmEnDATIOn cOmmITTEEProf.dr. r.e. BontropProf.dr. F. claasProf.dr. m.r. dahaProf.dr. c.g.m. KallenbergProf.dr. g. KraalProf.dr. r.a.W. van lierProf.dr. c.J.m. meliefProf.dr. d. roosProf.dr. J. van de Winkel

EDITOR In chIEfdrs. l. van der ent

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IMMUUN October 2015

dutch society for immunology

Theme: cross-disease immunology

20ECI 2021

AmsterdamBuilding bridges

8Linde Meyaard

Activation &inhibition

4Column

News

16Paul-Peter Tak

Effectivepharmaceutical pipeline

28Joris Mooij

Causal Discovery

24Jules Hofmann

Immunityand the fly

7News

Agenda

14Immuno Valley

Ready for the future

26CTMM

From droplet to diagnosis

11Dominique Baeten Why doesn’t it work?

health.gsk.nl

NL/

PHCA

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6/15

. pro

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li 20

15

22Sanquin

Monitoringof biologicals

19ECI

Dutch immunology in Vienna

4 IMMUUN Maart 2015 5October 2015 IMMUUN

Dear reader,

I have exciting news to share: the Dutch Society

for Immunology has won the bid to organize the

6th European Congress of Immunology in 2021. The

congress will take place in our capital, the city of

Amsterdam. Professor Marieke van Ham PhD of

Sanquin has agreed to act as president.

The Board of the Dutch Society for Immunology is

delighted and honored to be trusted with the organization

of this important congress. We will do our utmost to make

it an event that will inspire immunologists from around

the globe. As a 50 year old, flourishing society we have

every confidence of succeeding in this ambition.

Congress theme will be ‘Building Bridges’: we want to

bring immunologists from all EU-countries together

and stimulate connections between young and

established scientists as well as between fundamental

researchers and clinicians. We think this is the best way

to advance fundamental, translational and clinical

research, resulting in applications that benefit society.

In 2016, we prelude on this collaboration by organizing

our annual congress together with the British Society

for Immunology (BSI). You are all cordially invited to

come to Liverpool to partake in lectures by leading

immunologists and in joint sessions of British and

Dutch researchers.

First, however, I hope to meet you at the NVVI Winter

School at Noordwijkerhout on December 16 and 17. With

keynote speakers Jacques van Dongen (Erasmus MC),

Karin de Visser (NKI Amsterdam), Linde Meyaard (UMC

Utrecht) and Maria Yazdanbakhash (LUMC Leiden) as

well as Van Lochem Laureate Sjaak Neefjes the program

is impeccable.

See you all at Noordwijkerhout!

Reina Mebius, president

NVVI/Dutch Society for Immunology

COLUMN

Building Bridges

edItOrIaLNeWS

Galapagos NV announced on July 15 that it has entered into a licensing agreement with the HUB foundation for use of Organoid Technology for pre-clinical research in cystic fibrosis (CF) and inflammatory bowel disease (IBD). Organoids are mini-organs grown in cell culture from biopsies taken from patients; these mini-organs faithfully recapitulate the genetic and phenotypic characteristics of diseased tissues. Organoids have proven to be valuable disease models for the high-throughput screening and validation of innovative medicines, bypassing limitations associated with cell-line and xenograft-based pre-clinical drug studies.Onno van de Stolpe, CEO of Galapagos, said: “The HUB’s Organoid Technology will add an exciting and cutting edge approach to Galapagos’ arsenal of research methods and potentially accelerate the discovery and development of our innovative drugs for CF and IBD.”“We are pleased that the HUB and Galapagos have entered into this license agreement”, said Prof. Dr. Hans Clevers, Board Member of the HUB. “This partnership underpins the unique contribution of Organoid Technology to the development of drugs for patients with unmet medical needs, including patients with CF and IBD.”

In NRC August 1, 2015 an interview with Els Goulmy by Ellen de Bruin was published entitled: ‘Look, a woman among the professors in toga!’ Here she reveals the secret behind her first success. She was trained as an analyst, and hired by transplantation pioneer Jon van Rood. ‘I wanted to do scientific research’, Goulmy tells, ‘but initially I was assigned to a routine lab. I instantly proclaimed that it didn’t captivate me. Upon this, Van Rood left me the choice: either quit or attain success with a new technology within a month.’ She chose the latter and made it into Nature with her research a few years later. Els Goulmy

galapagos licenses organoid Technology

from the huB foundation

It is with great sorrow that NVVI has learned that Dick van Bekkum (1925), one of the founders of the Dutch Society of Immunology, passed away on July 17. We remember Dick for his inspiration, dedication, perseverance and commitment for the Dutch immunology. After his retirement he remained very much involved in the area of immunology and hematology. At the annual dinner of the Van Loghem awardees, this Spring, Dick van Bekkum was still very active and challenging in discussions on different aspects of science that were so close to his heart. He will be missed.

in memoriam Prof.dr. dirk Willem van Bekkum

dutch-australian collaboration

in cancer vaccinesCristal Therapeutics in Maastricht announces a collaboration agreement with Melbourne-based PX Biosolutions. Cristal Therapeutics brings in its CriVac® nanotechnology vaccine platform in the joint research and development for the design of innovative vaccines. This platform enables tailor-made development of well-characterized polymeric nanoparticles of a specific size, that allow optimal antigen presentation to dendritic cells. PX Biosolutions’ scientists have develo-ped and successfully tested DCtag™ vaccine formulations against various types of cancer. Joost Holthuis, CEO of Cristal Therapeutics says: “We are very excited about this collaboration that fits our strategy to set up product developments with companies active in the vaccine area. We are convinced that we can create additional value for patients and vaccine companies by development of superior vaccine products based on our CriVac technology.” Ann Meulemans, CEO of PX Biosolutions comments: “Our team is very enthusiastic about the possibility to enhance the flexibility of its DCtag™ platform by using the CriVac technology.”

‘innovate or quit’

auThor! opens a satellite location at Pivot Park

AUTHOR! from ‘s-Graveland, has opened a satellite location at the Pivot Park on Oss. The company is specialized in analysis and report of clinical drug studies in a broad sense.

rubicon for ‘stressed bone marrow, scarred heart?’

Among this year’s NWO Rubicon grants was one immunology topic. Vanessa Frodermann, MSC, from Universiteit Leiden will work at Massachusetts General Hospital, Harvard Medical School, Center for Systems Biology in the USA for two years to study Atherosclerosis. Atherosclerosis is characterized by a massive arterial lipid and monocyte accumulation and remains the leading cause of death. As current treatment is inadequate, she wants to establish new therapeutic targets by examining the role of stress-induced monocyte production by bone marrow progenitors.

6 IMMUUN October 2015 7October 2015 IMMUUN

AGENDA1 en 8 oktober 2015ELISA theorie; achtergronden en kwaliteitsaspectenCursusprijs € 720,- Hogeschool Leiden, CBDInformatie & inschrijving: [email protected]

2, 16 oktober, 6, 20, 27 november en 4 december 2015PathologieHogeschool Leiden, CBDCursusprijs € 1.950,- Informatie & inschrijving: [email protected]

8 & 9 oktobermucosal Immunology: cells living on the edgeErasmus MCwww.molmed.nl

2 en 9 november 2015Statistiek voor analisten Inschrijven vóór 21 september 2015Cursusprijs: € 740,- Hogeschool Leiden, CBD, website: [email protected]

3 november 2015 (startdatum)Labmanagement - communicatieHogeschool van Arnhem en NijmegenVier wekelijkse bijeenkomsten op dinsdag 9.00-13.00 uurLocatie: NijmegenKosten € 795,00Informatie en aanmelding: www.hanlifesciences.nl of E: [email protected]

3 november 2015 (startdatum)Labmanagement - ProjectmanagementHogeschool van Arnhem en NijmegenDrie wekelijkse bijeenkomsten op dinsdag 14.00-18.00 uurLocatie: NijmegenKosten € 825,00Informatie en aanmelding: www.hanlifesciences.nl of E: [email protected]

3 november 2015 (startdatum)Statistiek voor laboratorium medewerkers (basis)Hogeschool van Arnhem en NijmegenZes bijeenkomsten op dinsdag 18.00-21.00 uurLocatie: Amsterdam (Sanquin)Kosten € 782,00Informatie en aanmelding: www.hanlifesciences.nl of E: [email protected].

5, 12, 19, 26 november, 3 en 10 december 2015Basiscursus moleculaire BiologieInschrijven vóór 24 september 2015Cursusprijs: € 1.265,- Hogeschool Leiden, CBD, website: [email protected]

9 en 10 november 2015Workshop malaria Inschrijven vóór 28 september 2015Cursusprijs: € 935,- Hogeschool Leiden, CBD, website: [email protected]

NeWS

isa Pharmaceuticals: cancer Vaccines gain momentum

ISA Pharmaceuticals B.V. announced the publication of a comprehensive scientific review of therapeutic cancer vaccines on July 28. This review outlines the best available strategies for successfully eradicating tumors with immunotherapy. The article in The Journal of Clinical Investigation was authored by a group of scientists from the LUMC; lead author is Cornelis Melief, professor at LUMC and CSO of ISA Pharmaceuticals. The researchers point out that considerable progress has been made with therapeutic cancer vaccines, resulting in prolonged patient survival. They also have to conclude that most strategies have not resulted in objective, durable tumor regressions yet.

Crucial success factors

After investigating numerous studies, the authors have identified a number of crucial success factors for better clinical outcome in cancer immunotherapy by vaccination. These are: sufficient antigen concentration in dendritic cells, an effective route of administration, the use of an adjuvant that can stimulate dendritic cells, the choice of combination therapy and, above all, selection of the right antigen. “With few exceptions, the design of many cancer vaccines has fallen short of important parameters for success,” said Melief. “As an example, it is now clear that cancer vaccines need co-treatment and cannot be expected to work as a monotherapy. In peptide-based immunotherapies, we now know that only concentrated antigen sources such as DNA, RNA or synthetic long peptides can raise robust CD4+ and CD8+ T cell responses. But it is also very clear today that the best results can only be achieved by choosing antigens that are unique to the cancer, thereby avoiding central immunological tolerance.”

Personalized immunotherapies against neo-antigens

Ronald Loggers, CEO of ISA Pharmaceuticals, goes into ISA’s own developments: “We are (…) seeing impressive outcomes with our lead candidate ISA101, which targets cancers induced by human papillomavirus infection. In the light of recent findings, reviewed in the JCI article, we will also focus on neo-antigens, novel antigens arising from mutations, for the treatment of non-viral cancers. Like the viral antigens, the neo-antigens are not subject to central immunological tolerance of a thymic nature, and therefore vaccination against neo-antigens fosters T cells with strong cancer killing capacity. As they are patient-specific, our synthetic long peptide (SLP®) approach is well suited for the design of personalized immunotherapies against neo-antigens.” ISA expects that the validity of its SLP platform is expected to be further strengthened by early 2016, when immune response data and early clinical observations will be evaluated from the Phase 1/2 CervISA trial. In this study, late-stage HPV16 positive cervical cancer patients are treated with ISA101 in combination with standard of care chemotherapy.

19, 24 en 26 november, 1, 3 en 8 december 2015Diagnostiek van veel voorkomende schimmelinfecties Inschrijven vóór 8 oktober 2015Cursusprijs: € 1.520,- Hogeschool Leiden, CBD, website: [email protected]

21 & 22 november 2015Een Leven Lang LongenLocatie: AlmereNRS, www.nrs-science.nl

23 en 24 november 2015Workshop Primer en probe designInschrijven vóór 12 oktober 2015Cursusprijs: € 755,- Hogeschool Leiden, CBD, website: [email protected]

24 november 2015 (startdatum)ImmunologieHogeschool van Arnhem en NijmegenVijf bijeenkomsten op dinsdag 18.00-21.00 uurLocatie: Amsterdam (Sanquin)Kosten € 552,00Informatie en aanmelding: www.hanlifesciences.nl of E: [email protected].

24 & 25 november 2015cancer vaccine conferenceFelix Meritis, Amsterdamwww.angiogenesis.nl

15 december 2015 (startdatum)Labmanagement - KwaliteitszorgHogeschool van Arnhem en NijmegenVier bijeenkomsten op dinsdag 14.00-17.00 uurLocatie: NijmegenKosten € 795,00Informatie en aanmelding: www.hanlifesciences.nl of E: [email protected]

16 & 17 december 2015nvvI WinterschoolLocatie: Noordwijkerhoutwww.dutchsocietyimmunology.nl

12 januari 2016 (startdatum)ImmuunhematologieHogeschool van Arnhem en Nijmegen16 bijeenkomsten op dinsdag 18.00-21.00 uurLocatie: Amsterdam (Sanquin)Kosten € 1.480,00Informatie en aanmelding: www.hanlifesciences.nl of E: [email protected].

26 januari 2016 (startdatum)Research ImmunologieHogeschool van Arnhem en Nijmegen6 bijeenkomsten op dinsdag 18.00-21.00 uurLocatie: Amsterdam (Sanquin)Kosten € 699,00Informatie en aanmelding: www.hanlifesciences.nl of E: [email protected].

Q-support sponsors four Q-fever studies

In 2013 The Ministry of Public Health, Well-being and Sports initiated the independent association Q-support to sup-port Q-fever patients. Q-support now sponsors four studies into the Q tiredness syndrome and chronic Q-fever, which latter can cause inflammation in blood vessels and heart valves. Researchers at Jeroen Bosch Ziekenhuis (JBZ) in ‘s-Hertogenbosch aim at finding chronic patients who have not been diagnosed yet. For a year they will screen all heart valve patients in Bernhoven Hospital for chronic Q-fever.Utrecht UMC will establish a treatment strategy for chronic Q-fever patients. Previous research has learned little about chronic Q-fever as treatment results were hardly analysed systematically yet.VUmc will investigate whether knowledge and developments derived from cancer therapies can be a first step in developing better drugs for especially chronic Q-fever treatment. Last but not least, RadboudUMC will carry out meta-analysis on the data about the Q-fever outbreak in the Netherlands in order to establish consequences such as tiredness, quality of life, psycho-social performance, general health problems, and experience of illness and work on the short and longer term.

More info: Q-support, Annemieke de Groot, T 073-6100010, www.q-support.nu.

Leiden University and Leiden University Medical Center (LUMC)

are seeking commercial partners for collaborative development

or licensing on a number of innovative technologies. Luris is the

Knowledge Exchange Office for both organizations and offers a

number of licensing opportunities in the area of immunology or

relevant to immunology research. Some examples:

Potential Rheumatoid Arthritis treatment (ref. MC073)

Leiden and Nijmegen scientists have discovered potent PAD-

inhibitors. These compounds are regarded to be potential

Rheumatoid Arthritis-drugs because they inhibit the cause of the

Rheumatoid Arthritis –cycle. Since these inhibitors intervene with

the cause of the cycle rather than suppress RA-related symptoms,

effective PAD inhibition may not require prolonged medication.

These inhibitors thus have a very promising potential first-in-class mechanism of action.

AON mediated exon skipping in the treatment of Rheumatoid Arthritis (ref. MC210)

LUMC scientists have designed two types of AONs for the treatment of inflammatory diseases. One is able to specifically decrease the levels of C5a and the second is able to increase the levels of sIL-1RAcP.

Mouse model to test the efficacy of therapeutic antibodies (ref. MC223)A new mouse model was developed expressing human Fc receptors. Over the years, a lot of therapeutic antibodies have been developed and marketed. These antibodies have the capacity to treat diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis and several forms of cancer.

licensing opportunities from leiden


Two decades ago, she was intrigued by the basic question how the immune system is switched off after activation. At present

Prof. Dr. Linde Meyaard of the Wilhelmina Kinderziekenhuis (WKZ) in Utrecht closely collaborates with clinicians on potential

therapies for RSV infection, SLE and vascular disease on the basis of this research line. On the road, Meyaard encountered a lot

of skepticism regarding her working on diseases seemingly far apart. Not from the part of clinicians, though. “I think it’s all-

important for both ends, the basic science and the clinical knowledge, to meet.”

tHeMe: CrOSS-dISeaSe IMMUNOLOGY

and the organs involved are totally different, but it is all about the same molecules and about the same approach to turn on these receptors.”Recently a third potential field of application was explored: vascular disease. “Arterosclerosis and myocardial infarction, are immune related heart diseases”, says Meyaard. “We closely collaborate with prof. dr. Gerard Pasterkamp in this here at the UMCU. We’ve seen to it that our receptor manipulation approach is translated in knowledge and tools that can relatively easy be transferred to a new field of application. Pasterkamp’s group makes use of the same mice as we do. We use them for our infection model and his group to do research on vein occlusion. Although these models are of a completely different nature, it turned out we share our view on how inhibition of inflammation could work out on disease.”Recent progress in her research has brought Meyaard closer to translational research. “I think it’s all-important for both ends,

the basic science and the clinical knowledge, to meet. As basic scientist you have the insight in the mechanism, clinicians have the prepared mind to connect this knowledge to what they see happening in patients. What appears to be illogical to me, can be perfect logic to the clinician. Of course it can be necessary to gain insight in the splendid isolation of the lab, but once you’ve acquired this insight, please go talk to clinicians. Keep on exchanging views, as you will only find connections if you are open to each other’s ideas.”In Meyaard’s situation, working on a mechanism that influences so many processes in different diseases, she has no choice but to collaborate. “But then again, the same goes for many other processes in immunology and thus for many other immunologists. Communication is the key to application; you have to meet people to become aware of the opportunities. Nowadays more and more immunologists realize this and this has broadened the scope enormously. Yet, there is still more ground to be won in this respect.”

A normal functioning immune system is switched on when pathogens such as bacteria, fungi or viruses threaten to invade the body. Receptors, proteins on the immune cell surface, detect the threat and alert the system to take action. But once the immune system has done its job and the threat has been removed, how is it turned off again? “Surprisingly, this question has for long received less attention from immunologists than immune activation. The basic question how this switch-off mechanism works, however, has intrigued me since 1996”, says Meyaard. Her starting point was therefore a concept, not a technology or a disease. Inhibitory receptors on the cell surface transfer signals to slow down and eventually stop the immune activity, to prevent immune action to evolve to immune pathology. Inhibitory receptors are switched on, they bind to ligands, to start a braking action on immune cell activity. It is, by the way, not a mere on/off switch but a balancing mechanism. Compare it to a volume control. “It is all about the balance between activation and inhibition”, Meyaard explains.

Genome screening has brought to light that there are about three hundred DNA sequences potentially coding for these volume controls. “As immunologists, we have characterized about sixty of these. Each immune cell has at least one of these inhibitory receptors, but often they have several”, she says. Some of these receptors have the task to make activation more difficult – an thus to prevent so called ‘bystander activation’. The braking and activation mechanisms are quite delicate and can become derailed. All autoimmune and inflammatory diseases spring from some unbalance in the immune system. Meyaard adds: “Disease can also originate from the vehemence of an in itself justified immune response against pathogens, which is for instance the case with sepsis.”

Sloppy immune cells

Another clear example of activation-inhibition dysfunction is the respiratory syncytial virus (RSV). “Practically everybody is infected with this virus, but most people won’t notice”, says Meyaard. “Some children, however, have to be hospitalized because of RSV. World-wide it even is a considerable cause of death among infants under two years of age. It turns out that the lungs of hospitalized kids are packed with activated neutrophils, a type of white blood cells, which create havoc. This damage can be lasting and may well lead to asthma. When these kids are hospitalized , the disease is already advanced. Anti-viral drugs will stop the virus, but not the immune response. Wouldn’t it be better to also treat them at this stage by trying to regulate the activation-inhibition mechanism?”That is what Meyaard currently works on, in close cooperation with WKZ pediatric infectious disease specialist prof dr. Louis Bont. “Neutrophils are a sloppy kind of immune cells, that fight bacteria on the basis of their sheer numbers. While killing bacteria, they will also damage surrounding healthy tissue. That is when immunopathology starts. Turning neutrophils down can be regulated for instance by two receptors I found long ago, which are called SIRL-1 and LAIR-1.” The Meyaard lab works with RSV-patient’s cells yielded from ventilation tubes to isolate the necessary cells for functional tests: can neutrophils helped to be switched on and off? After this in vitro manipulation, the researchers can start to find out whether the SIRL-1 and LAIR-1 receptors can have the same effect in mice. “This should eventually lead to application. Recently we signed the first contracts with industry for in vivo experiments with antibodies to see whether these can switch on the inhibitory receptors and thus switch off the pathogenic immune reaction .”In twenty years this research line has come all the way down from basic research to the start of preclinical experiments – although clinical application is still far, far away.

Meet clinicians

At the same time, besides RSV, Meyaard is involved in SLE (lupus) research in collaboration with rheumatologists. “The disease

The delicate balance between activation and inhibition

“The diseases and the organs involved are

totally different, but it is all about the same

molecules.”

Linde Meyaard: “Communication is the key to application.”

(Photo Bureau Lorient Communicatie)


Almost indecent

In the past, when working on one disease, it was far from obvious to apply for grants regarding research on other diseases. “I noticed it was sometimes almost regarded as indecent to do so. The suspicion sometimes clearly was that my application was bent towards this other disease just to get to any funding available”, Meyaard remarks. The success of anti-TNF for treatment of rheumatism, but also Crohn’s and psoriasis has started to change that situation. More recently the spectacular results with biologicals in general and immunotherapy against cancer in particular, has given another boost to the acceptance of the idea that the same mechanism can play a role in various diseases and thus that one key can sometimes open many windows of opportunity for treatment. Meyaard: “Anti-CD20 B-cell depletion has proven to work against tumors as well as against immune-activation diseases such as SLE. While the number of examples grows, the concept of generally applicable mechanisms trickles down and becomes accepted.”The non-hypothesis driven, systemic approach is hip and happening at present: to chart all processes and to measure the differences. “I don’t work that way myself, but I certainly recognize the value of that approach. I would even say that hypothesis driven research, the systemic approach and clinical knowledge together are the golden triangle for progress in medicine. When systemic researchers stumble on a molecule of which I happen to know a lot, we can help each other. There is no reason why one approach should exclude the other.”

On the bedside table

Meyaard has noticed that the recent recognition of the potential of regulatory receptors means a world of difference when it comes to opening doors. “Formerly, I frequently received reactions such as: ‘Interesting what you do, but what is it good for?’ Now people realize that the PD1 and CTLA4 activating receptors that play a role in anti tumor immunotherapy are in the same class of receptors as the inhibitors LAIR-1 and SIRL-1. It is no coincidence that during the last two years I was approached spontaneously by interested industrial parties frequently. Before, that it didn’t happen. It seems that I’m no longer the only one to have high hopes for a role of these receptors in targeted immune suppression.” When she started out, Meyaard never had a particular disease in mind. “But I must admit that it would make me awfully proud when my research would eventually result in a product on people’s bedside table. It would be different from a trail ending with a publication in Immunity or Nature Immunology as the ultimate goal. This doesn’t mean that one should go all the way to the clinic by oneself. But I think it’s worthwhile to actively search for a ‘warm transfer’ of a finding, to know that someone else’s capable hands can bring your findings towards clinical application.”

Leendert van der Ent

10 IMMUUN October 2015

[Nederlandse samenvatting]

De aan- en uitknoppen van het immuunsysteem

Twintig jaar geleden richtte prof. dr. Linde Meyaard van het Wilhelmina Kinderziekenhuis (WKZ) in Utrecht zich met haar basale onderzoek op de vraag: ‘Hoe schakelt het immuunsysteem eigenlijk uit als actie niet meer nodig is?’ Het aan- en uitschakelen bleek te werken als een soort vo-lumeknop die de sterkte van de afweerreactie bepaalt. De signalen voor dat uitschakelsignaal komen van receptoren op het oppervlak van immuuncellen. Inmiddels blijkt dat het niet goed uitschakelen van het immuunsysteem een rol speelt bij verschillende ziekten. Zo kan het dat Meyaard inmiddels in nauwe samenwerking met clinici betrokken is bij onderzoek naar RSV-infectie, lupus (SLE) en naar vaat-ziekten. Tot voor kort zag lang niet iedereen de logica in van betrokkenheid bij zulke uiteenlopende ziekten, vertelt Meyaard. Dat is veranderd door het succes van anti-TNF-behandelingen, die naast reuma ook bij de ziekte van Crohn en psoriasis kunnen aanslaan, en door de recente suc-cessen op het gebied van immunotherapie tegen kanker. Meyaard vindt het heel belangrijk dat immunologen vanuit hun fundamentele veld regelmatig overleggen met clinici om te bekijken wat de rol van algemene immunologische mechanismen bij verschillende ziekten zou kunnen zijn: “Communicatie is de sleutel naar toepassing.”

The Meyaard lab works with RSV-patient’s cells yielded from ventilation tubes to isolate the necessary cells for functional tests: can neutrophil granulocytes helped to be switched on and off? (Photo Bureau Lorient Communicatie)

“The antibody proved to be safe and effective

for patients with ankylosing spondylitis.

results were similarly positive in more than

1000 patients with psoriatic arthritis.”

Dominique Baeten focuses on the immunopathology of chronic inflammatory arthritis, in particular on spondyloarthritis (SpA) and rheumatoid arthritis (RA). In SpA, he and his team study the cellular and molecular mechanisms driving inflammation and tissue remodeling in the synovial tissue of the inflamed peripheral joint. Both human tissue biopsies and experimental animal models are used. There is also a clinical part to his SpA research. This is focused on the development of diagnostic biomarkers for SpA and proof-of-concept trials with novel targeted therapies. As to RA, Baeten’s team studies in both humans and animal models the B cell auto immune response to citrullinated proteins, especially the antigen presentation and cytokine production of autoimmune B cells. “We also study B cell growth factors and signaling molecules that are implicated in the pathological memory B cell response in RA”, he says.

Cellular and molecular immunopathology

Since 2006, Baeten has been focusing on the early and pre-clinical phases of spondyloarthritis and rheumatoid arthritis, for early diagnosis and preventive treatments. He works at the intersection of spondyloarthritis, Crohn’s disease and psoriasis. He is intrigued by the overlap and the differences between these diseases. “Why does an antibody work in one disease and not in another? They’re family! Unraveling the cellular and molecular immunopathology of these diseases would benefit diagnosis and treatment – especially with biologics.” We have to rely too much on trial and error in life sciences research. “It is so difficult to predict the success of a therapeutic

intervention”, Baeten says. “Even if we do understand the mechanisms involved, we are often surprised by the effect of interventions.”

One of the explanations is that mouse models have their limits when it comes to predicting effects in men and too little research is being done in actual patients. A same cell, cytokine, or pathway may operate completely differently depending on the exact immunological and tissue context. “Researchers aren’t too fond of the tedious work of describing human biopsies. That’s comprehensible: it will not get you a publication in a

It remains difficult to predict the success of a new targeted

therapy, such as an antibody, in a specific disease. What

functions well in a mouse model, may not function at all in

man. If tested in a variety of related diseases, the antibody

may also prove effective in another disease than expected.

Dominique Baeten, professor in Rheumatology at AMC-

UvA, proved the antibody Secukinumab to be effective

in Bechterew and psoriatic arthritis, with important

benefits for patients. “But I would so very much like to

know why it doesn’t do anything in Crohn’s disease. That

would shed light on the general mechanisms and help us

target our research.”

Prof. dominique Baeten, amc-uva

“i would so very much like to know why a therapeutic

antibody doesn’t work”

Dominique Baeten: “Novartis had developed a human monoclonal antibody

that selectively neutralizes IL-17A. Novartis did not know in what disease it

would prove effective. A research program was started in multiple hospitals.

At the AMC, we hit the jackpot.”





leading magazine. Still, it’s extremely important to understand if and how the mechanism which you studied in vitro is also operating in this particular pathophysiological setting.”

Compare biopsies

Baeten and his team therefore take tissue biopsies of patients with Bechterew’s disease and compare them to tissue biopsies of patients with RA. “We also take skin biopsies of patients with psoriasis and colon biopsies of patients with Crohn’s disease. We know that Bechterew is not related to RA, but psoriasis and Crohn’s disease are. If we would find cellular or molecular players in patients with Bechterew, Crohn’s or psoriasis that we do not find in patients with RA, this might help us understand the underlying mechanisms better. This is of course based on the assumption that what is important for Bechterew is not

important for RA. And if there is an overlap between Bechterew & Crohn, we expect to see the same mechanisms, cells and proteins playing an important role in both diseases.”

IL-17A

In 2006, when Baeten started his career at AMC, there was no research program for Bechterew. Today, Baeten is principal investigator of an impressive number of studies, one of which is related to the role of IL-17, a cytokine that plays an important role in driving the immune response in inflammatory arthritic diseases. “At the time, Novartis had developed a human monoclonal antibody that selectively neutralizes IL-17A. Novartis did not know in what disease it would prove effective. A research program was started in multiple hospitals. At the AMC, we hit the jackpot: in a proof-of-concept phase 3 study and two sets of pivotal phase 3 studies the antibody proved to be safe and effective for patients with ankylosing spondylitis (Bechterew’s disease). We saw rapid, significant sustained response in the signs and symptoms in all patients. That’s great news, since not all patients respond to anti-TNF agents, the drugs that are generally used to treat ankylosing spondylitis.” But that was not all. The first results from the phase 3 trials were similarly positive in more than 1000 patients with psoriatic arthritis: rapidly significant and sustained improvement in signs and symptoms, physical function, and quality of life was achieved. Publications in The Lancet and the New England Journal of Medicine followed – the first article on Bechterew’s disease ever in the New England. Baeten: “We hope that next year the medication will be on the market.”

Missing out

The research sheds light on the mechanisms involved. “We now perform a number of follow-up mechanistic studies where we take biopsies from tissues before and after treatment and deduce as much information from it as possible. This information is shared with other research groups”, Baeten says. Sadly, this type of research is only done in the diseases where the drug seems to be effective. “Thus, we are missing out on an opportunity to derive crucial information. Why does the antibody work in psoriatic arthritis and in ankylosing

International experience

Dominique Baeten was born in Belgium. He was Professor at the University of Ghent as well as chef de clinique at the UMC Ghent. He then became a research fellow at the Institut National de la Santé et de la Recherche Médicale in Nantes, France before accepting a position at Harvard Medical School and Brigham and Women’s Hospital in Boston (US). In Ghent he worked on RA, in France on transplants and in the US on inflammation of the central nervous system. All countries have their pros and cons, Baeten finds. “In France, I discovered for example that the position of ‘ingénieur de recherche’ is an important one; a highly experienced researcher that does not have his own research group can be extremely useful.” He is less positive about the French bureaucracy and the lack of incentives to keep on working hard throughout your entire career. In the US, on the other hand, you’re under constant pressure to perform. In The Netherlands the balance is about right, he finds. Also, funding is fine and The Netherlands may be proud of the activity of health funds. Other strong points are the possibility to combine patient care and research and the international focus and open mindedness of the research community.Baeten would recommend all researchers to go abroad if the opportunity presents itself. “Everywhere you go, you meet new people and gain new insights. To me, this was immensely valuable.”

“We hope that next year the medication will

be on the market.”

spondylitis, but not in Crohn’s disease? These diseases are related. And why does it not work in RA or asthma? If we could figure this out, we would know a lot more about the mechanisms involved. It would allow more effective research and better targeted prescription.”The problem is that neither pharmaceutical companies nor health funds are too enthusiastic about funding this kind of research, since their focus is, understandably, more on achieving success at short term. Grants like the VICI and the ERC Consolidator – Baeten secured them both – are and will remain necessary for this fundamental research.

Alinda Wolthuis

Dominique’s pick:Three next big things in immunology:1. “There’s a lot in the pipeline for difficult-to-treat systemic inflammatory diseases like systemic lupus erythematosus.”2. “Clinical trials are being run with antibodies directed towards IL-23 (anti-p19) that frees more than half of the psoriasis patients completely from skin problems. The drug could be administered just once a year, instead of current treatments that work for one, two or four weeks.”3. “Immunotherapy in cancer, of course.”

Samenvatting

“Ik zou zo graag willen weten waarom iets níet werkt”

Het blijft moeilijk om het succes te voorspellen van een nieuwe therapie. Want wat goed functioneert in een muismodel, kan bij de mens totaal niet aanslaan. Als een antilichaam getest wordt bij verschillende verwante ziekten, kan blijken dat het ook effectief is in een andere ziekte dan verwacht. Dominique Baeten, hoogleraar reumatologie bij AMC-UvA, toonde aan dat Secukinumab zowel effectief is in Bechterew als in artritis psoriatica. Belangrijk en heel positief nieuws voor patiënten! “Maar ik zou ook zo graag willen weten waarom het niets doet bij de ziekte van Crohn”, zegt Baeten. “Dat zou licht werpen op de algemene mechanismen en ons helpen richting te geven aan het onderzoek.”

Baeten: “Why does the antibody work in psoriatic arthritis and in

ankylosing spondylitis, but not in Crohn’s disease?”


fungi and parasites, involve animal to human transmission. If partners in the Immuno Valley network combine forces in research and development, we might be able to find solutions and prevent transmission. Also, Immuno Valley partners can combine their knowledge and expertise on infectious diseases which have similar clinical manifestations in man and animal, like whooping-cough and kennel cough”, says Liana Steeghs. In 2008 this One Health approach was rather revolutionary. “Since then it has really taken off. This is also thanks to prominent Dutch researchers who have been promoting and spreading the concept”, Steeghs remarks. Another strong point of Immuno Valley is the focus on translational research and connection with the value chain. “We bring science and business partners together to learn from each other, to join forces and to speed up the application of research results.”

Network still growing

By 2015, Immuno Valley has grown into a strong network with forty partners. Various joint research projects have been started and large conferences such as the ALTANT (ALTernatives to ANTibiotics) Conference and the International One Health Congress have been organized. “We also organize annual meetings as well as thematic meetings for partners. These theme-related meetings take preferably place in-house at our partners”, says Liana Steeghs. “The meetings are a hit within the network. They often result in closer contact. Sometimes even new partnerships are forged in the aftermath. There is a tendency in companies to reduce their own corporate research effort in favour of cooperation with knowledge partners. We have proven that future partners find each other in Immuno Valley.”The number of industrial partners of Immuno Valley is still growing. Especially pharmaceutical companies and health-promoting companies such as nutritional specialists are joining the network.

Open to non-partners

Immuno Valley is now financially self-supportive. Liana Steeghs and her team organize events and theme meetings. They also initiate matches between partners, help partners organize funding for their projects and execute project management. Especially when three or more parties are involved in a project, the partners prefer Immuno Valley to step in as a neutral consortium manager. “In one on one matches our partners are perfectly able to organize collaboration according to their wishes. But when project environments become more complex it can be a challenge to organize funding, monitor the project progress and take care of

internal and external communication.” In respect to matters of Intellectual Property, Immuno Valley collaborates with the technology transfer offices of universities. So far, the Immuno Valley activities and services were exclusively carried out for network partners. From now on, non-partners can also appeal to the organization for specific services – in return for a fee. Services in the domains of funding, communication and dissemination of results, organization of events and proposal writing are from now on open to interested parties. Certain activities will however remain exclusively available for partners, such as participation in the Immuno Valley Council and access to events, meetings, newsletters as well as the Immuno Valley expertise database, giving online access to the available knowledge and expertise within the network.

Thumbs up

Immuno Valley has discussed the new way of working with existing partners as well as non-partners. “We got a ‘thumbs up’. All parties can benefit from this new way of working”, says Liana Steeghs. “Of course we hope to convince organizations to become a full member once they have experienced our service, but this may not in all cases be possible or desirable. In that case, we can help them out with certain services. At the same time, the overhead is shared by more parties. This adds sustainability to the business model.”Apart from ongoing activities, Liana Steeghs and her team have taken up the challenge to visit existing and prospective partners, take stock of their ideas and develop and execute new services. She focuses on knowledge institutions and on medium sized and large companies, as these have the largest demand for Immuno Valley’s services portfolio.“We are gearing up for the future. We have the ambition to turn the established connection between animal and human health partners into effective collaborations”, Steeghs says.

Since July 2015, Liana Steeghs is managing director of Immuno Valley. “Immuno Valley has momentum. We address urgent matters in the domain of human and animal health. Since our organization was established, in 2008, we have evolved into a vital network of science and business partners. It now is my privilege – and that of my team - to secure a sustainable future for the network.”

Connecting the chain

The increase of antimicrobial resistance and occurrence of zoonoses such as Q fever, Ebola and bird flu in the past decades prompted the thought that research into infectious diseases should not be restricted to either man or animal. “Zoonoses, caused by a range of disease pathogens such as viruses, bacteria,


With Liana Steeghs as the new managing director, Immuno Valley enters a new phase. Over the past years the organization

has developed into the national network on infectious diseases in man and animal. The network counts around forty partners

from academia and industry. Now Immuno Valley broadens its scope. The organization offers partners as well as non-partners

services such as consortium, project and event management, to create and support business-driven collaborations in research

and development.

The Immuno Valley team consists of managing director Liana Steeghs PhD and accountmanager Mijke Vogels PhD, both microbiologist by training and experienced in

consortium and project management. Senior communication advisor Denise van Heijningen MSc together with communication and project officer Aurélie Veltema BA,

are the experts in communication and event management within the Immuno Valley team. From left to right: Denise van Heijningen, Liana Steeghs, Mijke Vogels and

Aurélie Veltema.

immuno Valley gears up for the future

IMMUNO VaLLeY

Dit artikel is mede mogelijk gemaakt door Immuno Valley. Yalelaan 42 • 3584 CM Utrecht • The NetherlandsT +31 30 253 11 42 • M +31 6 205 412 89

Disease transcending approach

Tak found these developments so interesting, that he wanted to be part of them. He decided to switch from Internal Medicine to Rheumatology. At the AMC he was given the opportunity to set up a Clinical Immunology & Rheumatology department from scratch. After twelve years, this department had grown to a staff of 120. At this point he was approached by GSK to head global ImmunoInflammation research and development. By now, this unit has belimumab for SLE treatment as its first drug on the market, with a strong pipeline behind it.

“We will go wherever the science and unmet need will lead us”, Tak summarizes. “Up to now, this approach has for instance led to a clinical trial with a BET-inhibitor, interfering with epigenetic pathways, in NUT midline carcinoma patients, a type of cancer with a median life expectancy after diagnosis of only six to nine months, for which there has been no previous effective treatment. The FDA has even asked us to speed up development. The BET-protein plays an important role in the pathogenesis of this disease. The drug also holds promises for autoimmune disease treatment, but it is at first sight quite unpredictable what the risk-benefit profile would be. Therefore, we have decided to test it first in this rare form of cancer where a strong scientific rationale exists, to learn more about the risk-benefit profile of this treatment. This is a nice example of the value of a cross-disease approach on the basis of insights into underlying mechanisms.”Some of the future options are leukaemia treatment and perhaps the treatment or even cure of HIV. Tak explains: “The difficulty with HIV is that the virus may hide from eradication in a state of latency in reservoirs in the body. When you stop treatment, the disease comes back. A combination of broadly neutralizing antibodies or antiretroviral therapy with a cocktail of medicines including the BET-inhibitor might however create the necessary ‘shock and kill’ approach to decisively beat the virus. This is what is shown in humanized mice infected with HIV and reported by our unit in a recent paper in Cell.”

Turnaround to underlying mechanism

The best way to develop new medicines may be to focus first on the mechanisms and then find the best disease to treat with it rather

than the other way round. “Both the pharmaceutical industry and clinicians are only at the beginning of a turnaround in this direction. I sometimes have to push hard for this approach”, says Tak. “But the examples are there. TNF blockers were developed for treatment of sepsis, for which they didn’t work, but they were very successful in other immune-mediated inflammatory diseases. I plea for an approach that is fundamentally different from the conventional linear development of medicines: a strong focus on immunological mechanisms, finding the right diseases based on strong biological experiments with an emphasis on human biology, meticulous clinical observations, and experimental medicine studies to increase the confidence in the therapeutic target in specific diseases before traditional clinical development. This results in a cycle of in vitro and ex vivo research, mechanistic clinical trials and back to the lab to address new scientific questions. This cycle strengthens the confidence that a specific target is relevant in a given disease and helps to increase the insight into the underlying mechanisms.”

This new approach may also help to redefine syndromes defined by clinical signs and symptoms into specific subsets based on molecular patterns and response to targeted therapies. “And that is an important step towards individualized and personalized medicine”, says Tak.

Prevention

Back to rheumatoid arthritis. “Despite spectacular success, this disease cannot be sufficiently controlled yet. With the available therapeutic armamentarium, at least 50% of the patients will still have active disease at any time. Thus, the first goal is to be able to induce remission or absence of inflammation in all patients. Even better would be to achieve this goal without the need for continued chronic treatment, or cure. As a next step, we may start to think about interventions during the preclinical stage to prevent the development of clinical signs and symptoms. In case of rheumatoid arthritis and also type 1 diabetes and multiple sclerosis we are getting better at predicting which subjects are at risk of developing disease based on the presence of auto-antibodies and other features. This opens the way to preclinical intervention. We are presently running the first ever clinical trial with a biological to prevent


“The effect was so powerful, that double-blind trials could hardly be kept double-blind in practice”

The powerful effect of TNF inhibitors set Paul-Peter Tak on the track of immunology. Some years ago he made a second major

move: he chose for a position in the pharmaceutical industry to maximize his impact on patient’s lives. As Global Head of

ImmunoInflammation at GSK he explains his research focus on a cross-disease approach and GSK’s collaboration model. “We will

go wherever the science and unmet need will lead us”, Tak summarizes his present goal. Tak strives to overcome misunderstanding

between academia and pharmaceutical industry by stimulating collaboration.

“The best way to develop new medicines may be to focus first on the mechanisms and then find the best disease to treat with it rather than the other way round”

Towards a more effective pharmaceutical pipeline

Paul-Peter Tak wishes to bridge the gaps

During the last two decades, a revolution has been going on in the treatment of rheumatoid arthritis. Professor Paul-Peter Tak describes how he witnessed this change as an internal medicine specialist at LUMC: “Twenty years ago, there were waiting rooms full of wheelchairs and patients with severe malformations. Premature mortality was comparable to that of severe coronary disease or malignant lymphoma, whereas attention and funding were concentrated on vascular diseases and cancer. The impact of chronic diseases was – and still is – underestimated. I was touched by the suffering of patients with chronic disease.” Then treatment with biological TNF inhibitors came up. Tak: “The effect was so powerful, that double-blind trials could hardly be kept double-blind in practice. Patients and doctors alike saw the unusual effects. There were also other important

improvements in rheumatoid arthritis treatment. The life of the patients has changed radically since then. Wheelchairs in the waiting areas became rare over time – at least severe disability due to rheumatoid arthritis. It proved to me how powerful immunology research could be. Optimal treatment could bring patients in remission, just as can be the case in oncology.” Furthermore, the development of TNF inhibitors provided insight into the effect of targeted treatments in other chronic inflammatory conditions such as psoriasis, Crohn’s and ulcerative colitis. “Treatment of rheumatoid arthritis offered a prototype for the entire field of immune-mediated inflammatory diseases”,

Tak concludes. “This field was henceforth seen as one group with in part overlapping and partly different

molecular mechanisms resulting in different clinical manifestations.”


Paul-Peter Tak: “The first goal with rheu-

matoid arthritis is to induce remission or

absence of inflammation in all patients. As

a next step, we may start to think about

interventions during the preclinical stage

to prevent the development of clinical signs

and symptoms.”

(photo Bureau Lorient Communicatie)



Op naar een effectievere farmaceutische pijplijn

Paul-Peter Tak wil de kloof overbruggen

Het effect van anti-TNF behandeling zette prof. dr. Paul-Peter Tak op het spoor van de immunologie. “Het effect was zo sterk, dat dubbel blinde trials in de praktijk nauwelijks dubbel blind konden blijven.” Het AMC gaf hem de gelegenheid om vanuit het niets een afdeling Klinische Immunologie & Reumatologie op te zetten. Na twaalf jaar was deze afdeling uitgegroeid tot 120 medewerkers. Op dat moment vroeg GSK hem om hoofd Global ImmunoInflammation Research and Development te wor-den. Inmiddels heeft dit team belimumab tegen SLE als eerste geneesmiddel op de markt en een goedgevulde pijplijn erachter. Tak koos voor deze positie om een zo groot mogelijke impact op het leven van patiënten te hebben. Hij legt zijn onderzoeksfocus uit aan de hand van een ziekte-overstijgende benadering en het samenwerkingsmodel van GSK: “We gaan doen waar de weten-schap en de onbeantwoorde behoefte van patiënten ons leiden.” Hij streeft ernaar de bestaande misverstanden tussen academia en de farmaceutische industrie op te lossen door de wederzijdse samenwerking te bevorderen. “Deze benadering heeft een klinische trial met een BET-inhibitor opgeleverd, die ingrijpt in epigenetische pathways, in patiënten met NUT midline carcinoma patients. Dat is een zeldzaam kankertype met een gemiddelde levensverwachting van maar zes tot negen maan-den na diagnose, waarvoor tot nu toe geen effectieve behande-ling bestond. Enkele toekomstige behandelopties betreffen leukemie en misschien zelfs behandeling en genezing van HIV.

Een combinatie van over een brede linie neutraliserende antilichamen of retrovirale therapie met een medicijnen- cocktail die ook de BET-inhibitor bevat, zou de nodige ‘shock and kill’ benadering kunnen bieden om het virus beslissend te verslaan. Dat is aangetoond in gehumaniseerde muizen met HIV en daarover hebben we onlangs in Cell gepubliceerd.” Volgens Tak zou de beste manier om nieuwe medicijnen te ontwikkelen wel eens kunnen zijn om eerst te focussen op de onderliggende mechanismen, om vervolgens de meeste ge-schikte ziekte te zoeken voor behandeling, dan de omgekeerde weg die nu meestal wordt bewandeld. “Zowel de farmaceuti-sche industrie als clinici staan nog maar aan het begin van een ommezwaai in deze richting. Soms moet ik flink doordrukken om deze benadering geaccepteerd te krijgen”, zegt Tak. “Maar de voorbeelden zijn er. TNF-blockers werden ontwikkeld voor de behandeling van sepsis – waar ze niet tegen werkten – maar ze bleken uiterst succesvol in andere immuun-gemedieerde ontste-kingsziekten. Ik pleit voor een fundamenteel andere aanpak dan de conventionele lineaire medicijnontwikkeling: een sterke focus op immunologische mechanismen. Daarbij vervolgens de juiste ziekten vinden om te behandelen, gebaseerd op solide biologi-sche experimenten met nadruk op humane biologie, zorgvuldige klinische observaties en experimentele geneesmiddelen- studies om vertrouwen in het behandelingsdoel op te bouwen bij specifieke ziekten voordat traditionele klinische trials aan de orde komen. Deze resulteren in een cyclus van in vitro en ex vivo onderzoek, mechanistische klinische trials en weer terug naar het lab om nieuwe wetenschappelijke vragen te beantwoorden. Deze cyclus kan het vertrouwen versterken dat een bepaalde target relevant is tegen een bepaalde ziekte en helpt het inzicht in de onderliggende mechanismen te vergroten.”

rheumatoid arthritis at AMC. We expect to present the results of this PRAIRI-study later this year.” A similar approach can be envisaged in type 1 diabetes, and we started to explore the effects of the monoclonal antibody otelixizumab in very early type 1 diabetes. “This may be a new model for the pharmaceutical industry. The commercial model may be challenging, but it’s the right thing to do.”

This is the first part of an interview with Paul-Peter Tak. The second part will be published in the next issue, December 2015


4tH eCI IN VIeNNa

The Scientific Program Committee had compiled a highly stimulating program, covering the full spectrum of modern immunology. The program consisted of an EFIS Presidential Symposium, four keynote addresses and more than forty symposia with invited speakers. In addition, there were 72 workshops with oral abstract presentations and poster sessions. Recent advances in innate immunity, adaptive immunity, diseases of the immune system and modern forms of immune interventions were all represented and discussed. The congress was attended by around four thousand delegates from Europe and all other continents. More than three thousand abstracts had been submitted, 432 of which had been selected for oral presentation during the workshops. More than a hundred abstracts came from the USA and Brazil, more than seventy from Australia, and more than sixty from China, indicating that ECI has become a mature congress that receives worldwide attention.

Breakthrough to metabolic and neurological diseases

Grand old man among the invited speakers was Tasuku Honjo (Kyoto, Japan), who discovered the PD-1 gene in 1992. He gave a historical overview of how the discovery of this gene, that was originally thought to be involved in programmed cell death, after twenty years resulted in a revolution in cancer therapy. Anti-PD1 antibodies have now been approved for highly effective treatment of several types of otherwise untreatable cancers! He motivated his audience by arguing that immunology, after having yielded successful therapeutic strategies for infectious diseases, now does so for cancer, and in the near future will do for metabolic and neurological diseases as well. Several presentations at this congress indeed highlighted recent insights

in reciprocal interplay between metabolism and immunity, an area that has seen a remarkable renaissance in recent years.

Further increase possible

How was Dutch Immunology represented at ECI 2015? We can be proud of the fact that eight of the 76 invited speakers were Dutch Immunologists: Ton Schumacher, Reina Mebius, René van Lier, Linde Meyaard, Yvette van Kooyk, Hergen Spits, Jasper Koning and Mirjam Heemskerk. In addition, Fons van de Loo was invited speaker in a symposium organized by the European League Against Rheumatism, while Ronald van Ree presented during a meeting of the World Allergy Organization, both scheduled as Joint Symposia with ECI. On the abstract side, however, our country submitted only 68 abstracts, less than for instance Turkey and Iran. The quality of this input must have been high, as 20 out of 68 abstracts had been selected for oral presentation, more than double the average percentage. Erasmus MC, Rotterdam, presented six orals from the Departments of Immunology, Hepatology and Gastroenterology and Lung Diseases. Radboud UMC Nijmegen rendered five orals from the Departments of Tumour Immunology, Rheumatology, and Internal Medicine. They were followed by the Amsterdam AMC with three oral presentations. Finally, Henrike Veninga from the Amsterdam VUmc won one of the twelve poster awards. Last but not least, NVVI submitted a bid to host the 6th ECI in 2021 in the Netherlands, and this bid was awarded! Taking the high level of Dutch immunology research into account, it should be possible to further increase the exposure during future EIC meetings. Next opportunity: the 5th ECI meeting in Istanbul in 2018.

Jaap Kwekkeboom, Laboratory of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre, Rotterdam

4th european congress of immunology (eci) ample presence of dutch immunology in Vienna

The European Congress (ECI) is

organized every three years by the

European Federation of Immunological

Societies (EFIS). The fourth edition was

this year held from September 6-9 in

Vienna. Eight out of 78 invited speakers

were Dutch, a fact to be proud of.

Three persons from this group did oral presentations at the ECI in Vienne: second on

the left Patrick Boor, first from the right Guoying Zhou and third from the right Jaap

Kwekkeboom presenting work from Xiao-Lei Shi, second from the right.

Diseases of the immune system and Immune interventions. Each track will cover basic, translational and clinical immunology. The Dutch Society for Immunology encourages satellite meetings to connect immunology of different disciplines, to build even more bridges. The topics Veterinary Immunology, Immuno-senescence, immunology for oncologists, Immune reactions against biopharmaceutical and advanced cytometry are planned to be associated with the 6th ECI meeting in Amsterdam. Some of these satellite meetings will be organized based on the local interest in immunological topics in the Netherlands.

In addition, joint symposia will be included in ECI 2021. Societies such as the American Association of Immunology (AAI), the European League against Rheumatisms (EULAR), the International Union of Immunological Societies (IUIS), the European Academy of Allergy and Clinical Immunology (EAACI), the International Society for Advancement of Cytometry (ISAC), the European Society for Immuno-deficiencies (ESID) and the World Allergy Organization (WAO) are all invited to organise joint symposia during the 6th ECI meeting in Amsterdam. The Local Organizing Committee (see box) is determined to make ECI 2021 Amsterdam a memorable event for the European immunologists.


NeWS

SaNqUIN LICeNSeS ItS MHC IP POrtfOLIO fOr StIMULatION Of ONCO-IMMUNOtHeraPY deVeLOPMeNtStichting Sanquin Bloedvoorziening has granted Immatics Biotechnologies GmbH (Tübingen, Germany) a non-exclusive license for the use of its patented MHC T-cell technology to stimulate the development of immunotherapies in the fields of oncology and contagious diseases. Earlier this year Kite Pharma, a biopharmaceutical company aimed at the development of genetically modified products for autologous T-cell therapy, also entered a non-exclusive licency agreement with Sanquin Bloedvoorziening for the same technology by its acquisition of T Cell Factory BV.

Major histocompatibility complex (MHC) proteins on the cell surface bind to tiny protein pieces called peptides and present these to specialised immune cells. When such a peptide originates from for instance a virus or is tumour-specific, such a “cytotoxic T-cell” recognises the infected cell/tumuor cell and can kill it.

The licensed technology enables it to generate large series of peptide-MHC complexes quickly and easily for in vitro immunogenicity assays and for the identification of the related antigen specific T-cells in patient samples. Sanquin’s technology, developed in collaboration with the Nederlands Kanker Instituut, attracts large interest. The two license agreements in short notice are evidence of this; other parties have also shown their interest. The technology contributes to further optimisation of for instance onco-immunotherapy. In auto immune diseases research is also ongoing regarding this technology.

This ‘Building bridges’ is of course a metaphor. It is even a multiple metaphor. First of all, in a world in which national borders become more and more futile, it refers to building bridges between scientists throughout Europe, in order to reach breakthroughs in immunology together. On a second level, it stands for building bridges of knowledge exchange between experts on the innate immune system and the adaptive immune system, diseases specialists and disease intervention specialists. Thirdly, bridges between young and established researchers are important to bring the field further. For this low registration fees for young investigators will be set to help their participation. And last but not least, the bridges metaphor should be applied in close collaboration between basic science, translational research and clinical application. All these bridges play a vital role in speeding up innovation in a field that is so essential to people’s health.

Amsterdam’s attraction

In their plea for Amsterdam, NVVI chairman Reina Mebius, secretary general Edward Knol and treasurer Rene Toes pointed

at the multicultural, cosmopolitan nature of the city and at the open, tolerant, young-at-heart character of its inhabitants. Most of them speak at least two languages. With inhabitants from 177 different cultures Amsterdam ranks in the top three of most diverse cities in the world. Apart from that, there are also very practical reasons to choose for Amsterdam. An example of this is the city’s excellent public transport network and the eight minute link from the RAI convention centre to Amsterdam Schiphol Airport. Another example will be the new hotel in the RAI complex, providing an excellent location to stay for speakers, exhibitors and organizers, extremely close to the town centre.The City of Amsterdam is increasingly developing into a centre of knowledge and is already a major destination for international scientific conventions. The combination of stimulating scientific talent and first rate convention facilities can yield remarkable results. In order to stimulate these, the City of Amsterdam and its partners have set up the Amsterdam Young Scientist Award. Its aim is to stimulate and develop new talent within a scientific discipline. Hosting the ECI 2021 enables – within certain boundaries - the scientific committee to designate one of the most promising, participating scientists the winner of a EUR 5,000 award to be spent on research or attending conventions. In this way Amsterdam underlines how it values the international scientific conventions within its city limits.

Programme and Satellite Meetings

The programme of ECI in Amsterdam will cover four balanced tracks: Innate Immunity, Adaptive Immunity,

Pre-financing and guarantee

To organise ECI 2021, the Dutch Society for Immunology applies for the Pre-financing and Guarantee Fund (VGF). This initiative of the Netherlands Ministry of Economic Affairs, the Association of the Dutch Convention Industry (VNC) and the Netherlands Board of Tourism & Conventions (NBTC) offers organisers of international congresses in the Netherlands pre-financing and a guarantee.

Local Organizing Committee

The local organizing committee of ECI 2021 consists of Marieke van Ham (president) and will include Mihai Netea, Jannie Borst and Cees van Kooten. Also, all members of the board of the Dutch Society for Immunology have committed themselves to actively participate in the planning and organization phase for the European Congress of Immunology 2021 in Amsterdam: Reina Mebius (chair), René Toes (treasurer), Edward Knol (secretary), Martin van Hagen, Ton Langerak and Mieke Boots.

After an exciting competition with Dublin the European Federation of Immunological Societies (EFIS) has granted the organi-

zation of the sixth European Congress of Immunology (ECI) to Amsterdam. The city will be the focal point of immunology from

August 29th to September first, 2021. About five thousand immunologists from all over the world will gather at the capital’s RAI

convention centre. This meeting will be a unique showcase for Dutch Immunology. The Dutch Society for Immunology (DSI-

NVVI) has chosen a fitting theme for this venture in a city of islands separated by canals: ‘Building bridges’.

6th eci in 2021:Building bridges in amsterdam

[Pictures: RAI, Amsterdam]


Levels are key

Overtreatment can also be a health risk: adverse events may harm the patient. On the other hand, testing can also show too low drug levels. Schreurs: “Treatment should then be intensified or therapy adherence improved. It might also indicate that the biological is not effective and that a switch to other therapeutics should be considered.” A third possible result is that the patient does not respond to treatment because of anti-drug antibody formation, in this case a test for immunogenicity is required. Dr. Yvette van Hensbergen, head of Marketing at Sanquin Reagents, agrees with Schreurs. “Levels are key”, she says. “They show the patient’s response to treatment weeks before antibodies or clinical observations can.” She recommends testing from the start: “Treatment starts with the generic dose. Level testing shows whether the patient receives effective treatment. By fine-tuning the treatment interval or dose, the optimal level can be reached. If the patient responds, his/her quality of live can significantly improve. Testing helps doctors to decide whether the medication could be tapered or even stopped. If, on the other hand, symptoms reoccur, other treatment options should be considered.”

Test requirements

Tests should meet specific requirements, says Schreurs. “At the Erasmus MC we compared validated tests produced by different suppliers. A good test complies with the ISO 15189 standards, is user friendly and fits into the lab’s routine. The test should also be affordable, specific for the biological, easy to apply and most importantly, generate the information we need. Some tests

should be more sensitive than others, depending on the desired dose ranges in the patient. Finally, it helps when the same test is also used in hospitals we collaborate with. That enables us to compare results and together draw conclusions on the efficacy of treatment.”


In case of treatment with biologicals, ‘one dose fits all’ is still the leading principle. Marco Schreurs supports patient specific dosing, based on level testing. Although testing still isn’t standard procedure, doctors start asking for it more and more because they want to know whether treatment can be expected to be successful. “Scientific evidence exists that the effect of a biological can be very different per (group

of) patient(s)”, he says. “Drug level testing from the start of treatment enables doctors to optimize the dosage. Too high levels indicate that the dose intensity might be reduced or the treatment interval prolonged, resulting in a higher quality of life and reducing costs. Since biologicals weigh heavily on hospital budgets, the budget saved could be used to treat more patients.”

Therapeutic drug monitoring for patients treated with biologicals is vital, says Dr. Marco Schreurs, medical immunologist at

Erasmus MC. He supports level testing to investigate dose-effect and concentration-effect relationships. “Drug levels can be

effective indicators of the expected clinical effect of biologicals. Testing them enables accurate and patient specific treatment

decisions, resulting in optimized treatment and reduced costs.” Today, less than 10% of the patients is tested. And only 50% of the

requested tests is a level test.

START to test SMART

Sanquin developed the ‘START to test SMART’ testing concept for biologicals. By testing from the beginning, useful clinical information can be obtained and patient treatment enhanced. If customers have a relatively small amount of tests, samples can be sent to the Sanquin Test Service. Hospitals that need to perform these tests routinely, can test the samples by themselves. Sanquin offers ELISA test kits that are easy to perform, ready to use, with wide range and highly accurate. Most importantly, the results from the Sanquin Test Service and the Sanquin ELISA kits are the same, which makes it very easy to switch for the customer.

This article was made possible by Sanquin, www.sanquinreagents.com. For more information contact Yvette van Hensbergen, T 020-512 3100 or email: [email protected].

Biologicals: therapeutic drug monitoring is vital

Fotocredits: Marsprine / Marieke de Lorijn.

24 IMMUUN October 2015 25

sensing pathogenic microorganisms and triggering the immune system.”This was fascinating since, previously, the Toll pathway – discovered by Christiane Nüsslein - was known mainly for its contribution to embryonic development. “We have shown that it was also involved in immunity. We demonstrated that it served as a sensor, detecting infectious microorganisms and alerting the immune system to produce antimicrobial peptides.”

From flies to humans

Hoffmann’s research prompted the search for Toll-like receptors in mammals. It led to better understanding of the immune system and eventually to progress in treatment of anything from microbial infection to inflammatory diseases such as Crohn’s and cancer. A flux of 20,000 papers of clinical interest on the role of Toll-like receptors in inflammation, vaccination, autoimmunity, allergy, immunotherapy and infectious diseases underlines this. “Science has gone from flies to humans. The Toll pathway in flies, activated in response to fungi and Gram-positive bacteria, has significant similarities with the Toll-like receptor (TLR) pathway in mammals. The other pathway is the Drosophila immune deficiency (IMD) pathway that controls infection by Gram-negative bacteria. This pathway resembles the mammalian TNF-receptor pathway.”

Innate immunity on the map

Hoffmann stresses that he is not to be credited for the research in mammals: he has always restricted his research to insects. But his group’s contribution to the understanding of the immune system – Hoffmann constantly points out that fellow researchers have contributed significantly - has been recognized as revolutionary. It put innate immunity on the map. “At the time, innate immunity was not popular. The focus was essentially on adaptive immunity. There were few receptors known in innate immunity, none of which would single to NF-kB. Our research showed that the hallmark of the activation of two pathways was the activation of NF-kB and then control of gene expression.” Hoffmann’s research meant a major step in understanding innate immunity and gave a boost to understanding adaptive immunity. Hoffmann: “We discovered to our surprise that the innate immune pathways in flies and mice are highly similar. This raised the question when this system has appeared. We did datamining and, again to our surprise, found that all the molecules which we found in Drosophila are already present in sea anemones and mostly also in sponges, at the beginning of the evolution. They’re also present in worms, Crustaceans and vertebrates. Our research told us that the toolbox of the innate immune system was nearly fully present in the sea anemone one billion years ago, so that it has been well preserved in evolution. Over time, it was either simplified or diversified somewhat, but the important thing here is, that everyone seems to agree that full adaptive immunity in mammals requires the input from innate immunity. The innate immunity cascade in vertebrates has all the elements which we find in the fly today plus some additions absent in the fly today but present in sea anemones.”

Alinda Wolthuis

In 2011 the Luxembourg-born biologist Jules Hoffmann was awarded the Nobel Prize in Physiology or Medicine for having

revolutionized our understanding of the immune system by discovering key principles for its activation. Immuun met with the

Nobel laureate and learned how it all started with fruit flies. “The Drosophila, with its ancient immune system, has learned us a

lot about innate immunity and the role of the Toll gene in immune system activation.” It put innate immunity on the map.

October 2015 IMMUUN

A very happy moment

The Nobel Prize can be seen as a confirmation of the role of innate immunity, Hoffmann says. Looking back at the research that led to the prize: “It is the work of the laboratory, really. I had the vision of doing it this way, but we executed it as a team. It was a rather exciting period. Still, we were all hoping very much that our data would be confirmed by other colleagues. When Maniatis did this two years later it was a very happy moment.”

INNate IMMUNItY

Jules hoffmann

learning on the fly

Already as a youngster, Jules Hoffmann (1941) had a keen interest in insects. This childhood fascination would stay with him throughout his career. “Insects account for 80% of all living species. Via their vector capacities they put one third of humanity at risk of bacterial, fungal, viral and parasitic infections, yet they themselves are particularly resistant to all of these. One cannot help but wonder how their immune system works.”Hoffmann studied biology and chemistry in France and gained his PhD under Pierre Joly at Strasbourg University in 1969. While there, he worked as a research assistant for the Centre National de la Recherche Scientifique (CNRS). Building on Joly’s work with grasshoppers, Hoffman put the focus on the insect immune system, especially that of Drosophila. “We wanted to understand the mechanisms behind its immune response”, he says. In 1978 he established the Immune Response and Development in Insects unit at the CNRS. “We knew that, when we infected flies, a powerful antimicrobial reaction was induced. We wanted to establish the identity of the infected molecules and wanted to find out what triggers the receptor proteins of the immune system. Since fruit flies don’t have adaptive immunity, it would teach us how the innate immune system is activated.”

Toll gene triggering the immune system

The Hoffmann group discovered that Drosophila produces several families of powerful antimicrobial peptides. “Important to us was Diptericin, active against Gram negative bacteria. We then asked ourselves how the genes encoding those peptides are controlled.” Many of the flies bore genetic mutations, among them some with mutated Toll – a gene previously known to be important in embryonic development. Hoffmann: “When we – and I insist on the crucial contributions of my co-workers Jean-Marc Reichhart, Charles Hetru and Bruno Lemaître – infected the flies with bacteria or fungi, we discovered that mutations in the Toll signaling pathway left the flies more susceptible to fungal infection. Toll mutants died because they could not mount an effective defense. We concluded that the Toll gene was involved in

One of three: Bruce Beutler and Ralph Steinman

Hoffmann was one of three scientists to receive the Nobel Prize for Physiology or Medicine in 2011. Hoffmann conducted his research independently from Beutler, who discovered the mammalian homolog of Toll gene, the Toll-like receptors, in mice. The third person who received the Nobel Prize – albeit posthumously, since he died three days before the announcement – was Ralph Steinman, for his discovery of dendritic cells.

“We demonstrated that the Toll

pathway served as a sensor, detecting

infectious microorganisms and

alerting the immune system to

produce antimicrobial peptides”

27October 2015 IMMUUN26 IMMUUN October 2015

“it is often unclear whether patients have an

infection on arrival at the icu”

patient’s blood on arrival at the ICU. This blood analysis technique is based on the novel approach of recognizing the RNA signature of reaction to infection. “This approach still needs more evaluation before it can be introduced in the clinic”, Van der Poll concludes.

Pathogen recognition

Even closer to bedside application is an approach that focuses on the other side of the same coin, on the pathogen rather than on the patient’s reaction to it. Van der Poll: “Project partners Biocartis and Microbiome develop a molecular diagnosis test integrated in a lab-in-a-box device for pathogen detection. Ten millilitres of blood can be introduced to the device and the result can be read within two to three hours.” Both examples are a clear proof that the CTMM project goals are largely met.

Clinical trial approaches: Quick and accurate sepsis pathogen detection

Microbiome in Amsterdam is specialised in the development of molecular diagnostic tests for infectious diseases. “The CTMM MARS-project brought our expertise together with the equipment design and manufacturing skills of Biocartis and the clinical sampling of whole blood volumes at the AMC and University Medical Center Utrecht”, says Microbiome CEO professor Paul Savelkoul. “With use of this blood, we’ve developed a molecular test to quickly prove the presence of bacterial DNA in the blood.” Biocartis is building the Idylla™-Enrich and Idylla™ platform around this test. For the medical world, it is amazing what project partners have accomplished since the start in 2010. Savelkoul: “We hope to have a product on the market next year.”

The patient will benefit from this, says Savelkoul: “Typically, a ten millilitre blood sample is taken from a patient with the suspicion of sepsis, to start a two to three day culture. But as the clinician simply hasn’t got the time to wait for the results, the treatment is already started with broad spectrum antibiotics. We’ve designed a method to rule out this time consuming step by deploying Polymerase Chain Reaction (PCR) directly on bacterial DNA that is isolated from the blood without culture. Biocartis’ Idylla™-Enrich system destroys everything in the blood.” What remains is a bacterial lysate. The Idylla™ subsequently takes this bacterial lysate, isolates DNA en performs the PCR in a closed system to reveal the identity of the bacteria that are present.

Easy operation

This approach normally works with up to 1 millilitre of blood. For normal procedures, the bacterial load in 1 millilitre of blood is very low which is insufficient for detection. “Biocartis has designed a process to enable the analysis of ten millilitres, which suffices to detect the pathogen – and this within two to three hours.” The method can detect twenty five targets at once, covering 98% percent of all common sepsis pathogens. In addition, the most important resistance markers are covered.” Biocartis builds a fully automated platform around it. Operation requires no special laboratory skills. After elaborate testing at Microbiome and Biocartis, parallel to culture growth, clinical testing of the system will start in the second half of 2015 at Microbiome. Savelkoul: “We compare the outcomes of cultures with our approach. We’ve analysed only 300 out of 4,000 MARS samples so far, so I cannot speculate on the results.”

Positive impact

efore the MARS-project, there were no contacts between Microbiome and Biocartis. “The current close and fruitful collaboration between both companies inspires us to already think ahead toward future projects – there is for instance an urgent demand for a similar test aimed at neonates. The MARS-project enabled this strong combination”, Savelkoul concludes. Most important, he says, is the positive impact it can have on treatment. “According to clinical publications, the rapid results should have a positive impact on both morbidity and mortality caused by sepsis.”

Usually the body reacts to infections with an appropriate immune reaction. In some cases, however, the immune response is not balanced. It turns against the host, with the risk of causing tissue damage and organ failure. This is what we refer to as sepsis status. The sepsis status is a major cause of in-hospital morbidity, with an estimated 9,000 admitted cases of severe sepsis in the Netherlands. This number is rising due to an on average older population as well as growing numbers of patients weakened as a side effect of high-impact therapies against serious diseases. Sepsis can evolve from all sorts of infections, ranging from a perforated bowel to pneumonia. The mortality rate is high, especially in cases of septic shock - sepsis combined with a strongly reduced blood pressure. In 30-45% of cases this causes the patient’s decease. Current diagnosis options such as symptom scoring and bacterial culture techniques are both time consuming and not very specific.

“A key towards lower mortality is early diagnosis”, says professor Tom van der Poll, head of infectious diseases in the Academic Medical Center (AMC) Amsterdam. “There is an urgent need to speed up diagnosis – from days to hours – and to improve sepsis therapy.” That is why in 2010, the CTMM-project “Molecular Diagnosis and Risk Stratification of Sepsis (MARS)” was started. The project runs until mid-2015.

Infection detection

The AMC-part of the project aims at quickly measuring the host response. Van der Poll, Principal Investigator of the MARS project: “Patients who enter the Intensive Care Unit (ICU) are always critically ill. It is often unclear whether an

infection plays a part in their condition. Therefore we wish to quickly check for the type of the immune reaction and obtain insight in the prognosis. This would support our decision pro or con aggressive treatment with for instance blood pressure stimulants and artificial respiration.”Genome Techniques, based on bioinformatics, is the way to move forward in a rapid check. Van der Poll: “We are currently examining whether patient’s RNA expression profiles can be used to distinguish sub-groups with different prognoses. Indeed it looks as though patients with certain profiles have an unfavourable prognosis.” Two articles on this topic are by now under review. One of these, in which the project partner ImmuneXpress is involved, focuses on quick establishment of the presence (or absence) of infection in the

The CTMM-project Molecular Diagnosis and Risk Stratification of Sepsis

(MARS) addresses urgent challenges in sepsis treatment. Tools are needed

to provide rapid and accurate information about individual patients

to tailor treatment. Now that the project approaches its conclusion,

both a tool for determining which micro-organism is responsible for the

underlying infection and a tool for establishing the severity and stage of

the patient’s immune response are on their way to clinical deployment.

All these devices need is whole blood from suspected sepsis patients.

Professor Tom van der Poll: “It appears that RNA expression profiles

can be used to distinguish sub-groups of sepsis patients.”

(Photo CTMM)

Nederlandse samenvatting

Snel gericht ingrijpen bij sepsis

Het CTMM-project Molecular Diagnosis and Risk Stratification of Sepsis (MARS) is gericht op uitdagingen in de behandeling van sepsis. Er was bij de start in 2010 grote behoefte aan snelle, accurate informatie om patiënten op maat te kunnen behandelen. Dit leidt er naar verwachting toe dat er al binnen afzienbare tijd een apparaat van Biocartis op de markt kan komen met een moleculaire diagnostische test van Microbiome. Op basis van tien milliliter volbloed geeft het systeem binnen twee tot drie uur aan welke pathogeen er in het spel is, zodat de behandelend arts veel sneller gericht kan ingrijpen. Dat zou de mortaliteit als gevolg van sepsis omlaag kunnen brengen. Daarnaast is er ook een methode in onderzoek die de immuunreactie bij de patiënt meet, maar deze staat nog wat verder van marktintroductie.Dit artikel is mogelijk gemaakt door CTMM: www.ctmm.nl

cTmm

CTMM is dedicated to the development of Molecular Diagnostics and Molecular Imaging technologies, focusing firmly on the translational aspects of molecular medicine so that scientific results can be applied as quickly as possible in actual patient care. Achieving this objective could enable earlier and more precise diagnosis of disease and the design of highly personalized therapies. CTMM and TI Pharma are merging and will be named Lygature as of January 1st, 2016.

sepsis:

From droplet to diagnosis


Mooij’s research focuses on finding causal relations in data. This field exists for some decades now and is called ‘causal discovery’. The challenging part is – as everybody with a notion of epidemiology will know – that not all correlations are causal relations. Causal discovery deploys mathematics to discern correlations from causal relations.

In a nutshell

Mooij explains the basics and the history of causal discovery in a nutshell. “How can you find causal relations in observational data? Let’s say you have two variables, for instance smoking and lung cancer. The gold standard to find the causal relationship is to study the two variables in a randomized controlled trial. Human guinea pigs are randomly divided into two groups. An intervention is performed: one group is urged to smoke a lot, the other group is forbidden to smoke. If one group develops significantly more lung cancer than the other, one can conclude that smoking causes lung cancer.” It is exactly the unrealistic nature of this example that underlines the importance to work around the impossibilities of such an approach. Scientists would like to have the outcome of such testing, but ethics make it impossible to carry out such interventions. Mooij: “Some decades ago, researchers realized that an intervention could be unnecessary if one analyses observational data with at least three variables. Under the presumption that there are no confounders (unknown disturbing parameters), this in some cases enables conclusions on causality, based on statistical patterns in the observational data.”

Confounders

The presumption is of course the problem here – in complex systems it is hard to rule out the possibility of unknown variables playing some role. Mooij: “Arguably the most important finding in this field is that with a minimum of four variables, conclusions on causality can be drawn despite confounders. The mathematical model leaves room for hidden variables. Furthermore, the approach can be combined with experiments, which enables more reliable conclusions on causality, also when there are less than four variables.”

It was long thought that significant conclusions based on only two variables without intervention were impossible. Mooij: “We have recently shown that conclusions can be drawn with an accuracy of seventy per cent when considering only two variables at a time. There is room for discussion in which cases

that would be sufficiently accurate. Clearly, more variables enable more solid conclusions.” An interesting point is that, as in the Microsoft case mentioned before, causal predictions can be made. Mooij: “Once you charted a complex system, you can predict what happens when you perturb the system by intervening.”

Handling feedback

Sceptics may point at the complexity of the system, with feedback processes which are largely still unknown or not understood. How can predictions under such circumstances work out well? Mooij: “We are developing mathematical causal models that leave room for feedback loops, similarly to how we leave room for hidden variables. I would even like to turn this around: it is a benefit that the approach can handle part of a complex system without taking the complexity of the entire system into account. It even enables identification of unknown feedback loops from data. Our modelling approach enables to study only the part you are interested in, to draw predictive causal conclusions on this part and to leave the immense complexity of the biologic reality out of the picture. Predictions can prove wrong, but this offers opportunities to iteratively improve the model and henceforth to get better predictions.”


BIG data

Microsoft uses predictive causal modelling in order to foresee on what advertisements a user is likely to click. This is vital to the company’s business case, as every click means income. A prediction of how a parameter change influences business could replace elaborate in-practice testing of variants. As one of the variants is likely to be inferior, such testing would mean a suboptimal business performance during the test period and therefore missed turnover. Microsoft is investigating causal prediction methods as a more cost-effective alternative. How does this affect immunology? Although the field is entirely different, mathematically this case could resemble many of the challenges immunologists face. The similarities involve a complex decision model with several variables, uncertainty and especially big data. Mooij: “Causal discovery is applicable to all fields where causal relations are relevant, such as economy, social sciences and medical research. My favourite application area is biology, as it allows for reproducible validation of causal predictions.” Just as Microsoft would like to know what advertisement will make a certain user click, an immunologist would like to unravel the complex systemic difference between a healthy person and an individual with a certain affliction. Mooij: “If you chart the causal system of protein interaction in healthy people, you

can investigate what went wrong in people with a disease. Knowledge of the causal structure in protein interaction can also help to mend the system. It becomes possible to predict what happens when you influence the system, for example by administering a drug. What will happen and which drug candidate will perform best?”

Correlation or causality?

Another example. A mass cytometer can monitor the concentration of thirty proteins in ten thousand cells per second. The human mind cannot handle the amount of data generated in such a process. Hardware is currently developing faster than the software and algorithms for data analysis are. “We run the risk of lagging behind, which means not being able to use the available hardware to its full potential. We therefore urgently need software tools to automate the process of data analysis in order to arrive at causal models. Causal discovery in fact follows the same process that takes place in the head of the researcher: noticing patterns in data that justify causal conclusions”, says Mooij. “In present microbiology and immunology, data analysis approaches are in high demand. Generating big data is hardly a problem nowadays, but to make use of its potential added value is.”

The amount of data coming from for instance

a mass cytometer is staggering. How can

one discover meaningful patterns in such

vast datasets? “That is indeed challenging”,

Joris Mooij PhD, assistant professor at

the University of Amsterdam’s Institute

of Informatics says. “The classic research

approach of figuring out meaning ‘by hand’

does not scale up to big data.” Mathematics

and algorithms can be used instead, by

applying ‘Causal discovery.’

microsoft is investigating causal

prediction methods as a more cost-

effective alternative. how does this

affect immunology?

Who is Joris Mooij?

Joris Mooij PhD is assistant professor and data science researcher with life sciences affinity at the Informatics Institute of the University of Amsterdam. In 2014 he finished his VENI project ‘Cyclic Causal Discovery for Reconstructing Biological Regulatory Networks’ and started his VIDI project ‘Causal Inference: Theory for Applications.’ In 2015 he got an ERC Starting Grant for the project ‘Causal Analysis of Feedback Systems (CAFES)’.

Joris Mooij: “In

present micro-

biology and

immunology,

data analysis

approaches are

in high demand.

Generating big

data is hardly

a problem no-

wadays, but to

make use of its

potential added

value is.”

causal discovery:getting a grip on Big data


In contrast with systems biology, the field that tries to exhaustively describe the complexity and interrelations of a whole biological system, causal discovery methods enable reducing the complexity while still drawing meaningful conclusions. Mooij: “Causal discovery offers a way to efficiently handle the often underrated complexity of real systems. New discoveries prove every day that the complexity is larger than thought before.”

Mooij notices that the interest for causal discovery grows day by day, now the big data problem increases. “Presently we are on the threshold of a new way of doing science”, says Mooij. “Causal discovery offers the tools for this, although as a scientific field it admittedly still is in its embryonic phase. It is a big plus, on the other hand, that it fits to the immunologists way of working in a quantitative and automated way.”


NeWS


Greep op Big Data

De hoeveelheid data uit een massacytometer is verbluffend. Hoe kun je nog betekenisvolle patronen ontdekken in Big Data? Dr. Joris Mooij, UD aan het Instituut voor Informatica van de UvA: “Er ‘handmatig’ betekenis aan ontlenen lukt niet meer.” Hierdoor loopt benutting van het volledige potentieel van moderne hardware gevaar. ‘Causal discovery’ zou die trend kunnen keren. Mooij legt uit: “Als je het oorzakelijke systeem van eiwitinteractie in gezonde mensen in beeld brengt, kun je onderzoeken wat er mis ging in personen met een ziekte. Kennis van de oorzakelijke verbanden in de eiwitinteractie kan ook helpen om het systeem te repareren. Het wordt mogelijk om te voorspellen wat er gebeurt als je het systeem beïnvloedt, bijvoorbeeld met een geneesmiddel: welk kandidaat-medicijn werkt het best?” Causal discovery zoekt het antwoord op die vraag op dezelfde manier als de onderzoeker doet: patronen in data opmerken die oorzakelijke conclusies mogelijk maken. Minimaal vier variabelen maken conclusies over causaliteit mogelijk zonder dat onbekende variabelen die conclusies verstoren. Mooij: “Het wiskundig model laat ruimte voor verborgen variabelen. Verder kun je de benadering combineren met experimenten, waardoor ook oorzakelijke conclusies mogelijk worden bij minder dan vier variabelen.” Interessante aspecten zijn ook dat oorzakelijke voorspellingen mogelijk zijn en dat slechts een deel van een complex totaalsysteem zinvol onderzocht kan worden. Mooij: “Causal discovery staat nog maar aan het begin. Daar staat tegenover dat het past in de normale werkwijze van immunologen, maar dan op een kwantitatieve en geautomatiseerde manier.”

POSItIVe reSULtS ON NeW drUG fOr MULtIPLe MYeLOMa MONOtreatMeNt

Patients with relapsed/refractory multiple myeloma, the most common type of bone marrow cancer, may well benefit from treatment with the new drug daratumumab. It is estimated that 124,225 people will be diagnosed and 87,084 will die from the disease in 2015 globally. The cancer cells in the bone marrow largely disappear in close to forty percent of the patients that received the drug. The effect on this incurable disease lasts over a longer period. This initial Phase I/II clinical study initiated using daratumumab monotherapy, was carried out by the UMC Utrecht in collaboration with Harvard University and several Danish and Swedish academic medical centres. The full data set is published in the New England Journal of Medicine of August 27, 2015. 65% of the patients who responded to treatment in the 16mg/kg dose group in part 2 of the study did not experience disease progression twelve months after the start of treatment. Daratumumab has a tolerable safety profile and no maximum tolerated dose was identified. Following this study, 16 mg/kg was chosen as the dose to be used in future daratumumab clinical studies. Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. “Patients who have relapsed or refractory multiple myeloma currently have very limited treatment options. The results from this first-in-human study of daratumumab show an impressive response rate and duration of response, particularly when you consider that patients in the study had received a large number of prior treat-ments”, said Jan van de Winkel, Ph.D., CEO of Genmab.

The Art of Saving a Life

vaccines as Love Serum© Mauro Perucchetti

Mauro Perucchetti melds his classic resin sculptures into one big message for children’s health. In colorful pigmented resin, Mauro blends two of his best known sculptures: Jelly Baby Family, which embodies family unity and multiculturalism, and

Love Serum, that could “inoculate the whole world.” Mauro hopes the toy-like appearance of his work will help bring a smile to children, and eliminate fear of syringes and needles, while also eliminating the scepticism some parents have about vaccines. To tailor his work even more to the project, Mauro’s original Love Serum contained hearts, now transformed to happy faces,

and he has added a safety tip to the syringe so that no one pricks a finger. The work uses pigmented resin,stainless steel and a granite base, and stands about 14 inches tall.

The sculpture by Mauro Perucchetti is part of the ‘Art of Saving a Life’-collection commissioned by the Bill & Melinda Gates Foundation. More than 30 world-renowned photographers, painters, sculptors, writers, filmmakers, and musicians tell the stories behind the success and the future promise of immunization. Stories of risk and bravery, passion and

dedication of scientists, the love of parents, and the determination of health workers. Hear, see and feel the tremendous impact of immunization! W

ww

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tesf

ou

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on

.org

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IMMUUN€¦ · IMMUUN for every professional in the immunology chain Linde Meyaard The delicate balance between activation and inhibition Amsterdam hosts European Congress of Immunology