1. health and fitness
2. disease
3. cancer

IMMUUN
Volume 4 - Issue 1 - March 2015 -
for every professional in the immunology chain
Ton Schumacher:
“Immunotherapy has become a valuable
treatment option for cancer”
How to catch Circulating
Tumour Cells
Immunity and Science Fiction:
The next fifty years of
immunology research
Theme
Immunology and
Hidde Ploegh
cancer
Breaking new ground
Lia van der Hoek
Towards
identification of
all human viruses
Community of open innovation
What we are
Open innovation
More than just a workplace! Pivot Park is the pivot in
a flourishing network of companies and knowledge
institutions involved, either directly or indirectly, in
innovative research in the field of life sciences. We
provide accommodation to a diverse range of companies
with specialised knowledge in an open innovation
culture. Pivot Park provides ambitious companies in
the life sciences with access to the entire spectrum of
pharmaceutical R&D.
This open innovation and partnership extends
beyond the gates. Partners include companies and
the best departments of universities in the vicinity.
Pivot Park is not affiliated with any one university
or knowledge institute. We aspire to forge
partnerships on the broadest possible scale,
from the local to the international level: an open
community without borders!
What we offer
An exciting environment with a high quotient of
collaboration and diversity. New and existing life science
companies have every opportunity here to be inspired by
one another through networking sessions, project-based
partnerships or scientific conferences. The end result is a
stimulating cross-pollination that produces valuable input
for a healthy society. Pivot Park provides the foundation:
an optimal infrastructure, state-of-the-art facilities and a
wealth of knowledge and experience.
High quality facilities
We have state-of-the-art core facilities that we can
open to ambitious companies in the life sciences,
thanks to flexibility and customisation, with our
high-grade infrastructure providing a strong
launching point. This is targeted not only at start-up
companies, but also those wishing to take the next
step, with their often more complex needs.
www.pivotpark.com
COLOPHON
contents
IMMUUN March2015
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 BOARD
Dr. Godelieve de Bree
Prof.dr. Mieke Boots
Dr. Hans Jacobs
Dr. Edward Knol
Prof.dr. Yvette van Kooyk (chair)
Dr. Ingeborg Streng-Ouwehand
Dr. Andrea Woltman
4 7 18
24
20
28 30 34
News
Column
Agenda
News
Lia van der Hoek
Science across
borders
Schizophrenia
Portrait
Passion for research
Hidde Ploegh
Else Derks
recommendation committee
Prof.dr. R.E. Bontrop
Prof.dr. F. Claas
Prof.dr. M.R. Daha
Prof.dr. C.G.M. Kallenberg
Prof.dr. G. Kraal
Prof.dr. R.A.W. van Lier
Prof.dr. C.J.M. Melief
Prof.dr. D. Roos
Prof.dr. J. van de Winkel
editor in chief
Drs. L. van der Ent
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NVVI 50th
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Immunity
and Science
Fiction
Compare
Fighting infectious
diseases
Theme Immunology and cancer
11
8
Research
Cancer immunotherapy as
clinical reality
Jolanda de Vries
en Nicoline
Hoogerbrugge
Ton Schumacher
PHoto front page
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The world’s first preventive
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14
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DISCLAIMER
Immuun is made with the utmost
care. NVVI nor Bureau Lorient
Communicatie BV can be held
responsible or liable for errors.
Articles do not necessarily reflect
the opinion of the editorial board,
the publisher or the writer.
Immuno Valley
Award winner
Leon Verstappen
Circulating Tumour Cells
Detection and removal
17
Astrid Visser
Antigen-specific
immunomonitoring
22
Cancer
Immunology
research at
Pivot Park
dutch society for immunology
March 2015
IMMUUN
3
Column
Hunt for information
Cancer and immunology is undeniably a hot topic –
Connecting antibodies
and rightly so. The concept of helping a person’s own
immune system to battle cancer is extremely appealing.
Wouldn’t it be great if we could manipulate the human
immune system in a way to fight tumours? Research
results are promising, fueling hopes for a breakthrough.
Patients with a suppressed immune system – e.g. after
transplantation or immune deficiencies– are more likely
to get cancer than persons with optimally functioning
immune response. This is totally congruent with the
concept of empowering the immune system to battle
cancer. But it must be done in a very targeted way:
there is the risk of creating an imbalance. If the immune
system would become overactive, we can create auto
immune diseases.
It is therefore essential to thoroughly understand the
functioning of the immune system. In this respect, the
research on cancer immunology is extremely valuable as
well. Apart from its primary goal, which is to eliminate
cancer, it can improve our basic knowledge of the
immune system, thus providing us with new tools to
manipulate the immune system. The NVVI supports the
wish to improve our knowledge of the basic functioning
of the immune system.
Two antibodies that are connected have a much more powerful immune
reaction against all sorts of unwanted elements in our body than a single
antibody. But to make a strong connection is quite difficult. Researchers
of the AMC spin-off AIMM Therapeutics have succeeded in connecting
two antibodies against the flu, while retaining their function. “The
possibilities this method offers are unprecedented”, says Koen Wagner of
AIMM Therapeutics. “The benefits of bi-specific antibodies – as two linked
antibodies are called – are legion.”
You only need to administer something once and it has a much broader
function. But to connect the two antibodies is hard. Up to now, they
had to be adjusted in such a way that they lost their stability. As a
consequence, some antibodies were destroyed within two hours
after connection. Wagner learned from researchers in Boston how
two antibodies could be fixed with only minimal adjustments. Back in
Amsterdam he and his colleague Mark Kwakkenbos applied the method
to ‘two top-specimens’ that together can eradicate all type-A flu viruses.
Research in mice showed that the combination remains stable and offers
good protection, as could be read in a recent publication in the scientific
top-magazine PNAS.
“Bi-specific antibodies can be used for a lot more goals”, says Kwakkenbos.
“For instance in oncology, for fighting tumours. Once you can connect
antibodies, they become far more effective.” Wagner: “That goes in fact for
everything related to the immune system.” In order to let patients benefit
from this development, a lot more work has to be done. AIMM now starts
investigating whether the coupled antibodies can be produced on an
industrial scale.
It is vital that we exchange information and learn from
each other. We can and should do better. Congresses
usually focus on specific diseases, while combining
the knowledge on the underlying mechanisms that are
Source: AMC Magazine December 2014, PNAS publication, December 11, 2014 - A
bispecific antibody generated with sortase and click chemistry has broad antiinfluenza virus activity
operational in various diseases, is equally important.
Researchers are inclined to stay inside their disease
topics.
The NVVI urges researchers to broaden their perspective
and to hunt for information in other research areas
than their own. It is wise to gain insight into other
disciplines. Talk to your colleagues in and outside your
own institute and visit a congress in an adjacent field.
Cross borders and break down walls.
It also works the other way around. Maybe you know
an oncologist, a rheumatologist, a haematologist or
another specialist who could benefit from a better
knowledge on immunology? Encourage him or her to
learn more and to actively seek cooperation with you as
a specialist in immunology. The NVVI welcomes such
requests as well.
Reina Mebius,
Dutch Society for Immunology
4
IMMUUN
Maart 2015
Hans van Eenennaam, BioNovion:
“Start thinking from the end back”
In the Netherlands we have a huge amount of immunology knowledge.
This knowledge gives us an excellent position to make a difference in this
field. It would, however, be beneficial to both healthcare and economy
when more knowledge would be converted into bedside products. It is
common knowledge that there are hiccups in the value chain, but how to
identify, address and solve these? BioNovion COO Hans van Eenennaam
has a piece of the puzzle: “In many cases, researchers develop knowledge,
a target or a technology and only then start thinking of a product. Why
not do that the other way round, to start by thinking of an end product
all the way back to your own work. Ask clinicians and pharmaceutical
companies: what do patients need? What could my contribution
mean? What is already available and under development? What do
pharmaceutical companies demand from promising discoveries?”
NEWS
editorial
Binge drinking disrupts immune
system in young adults
Binge drinking in young, healthy adults significantly disrupts the
immune system, according to a study led by dr. Majid Afshar of
Loyola University Chicago Stritch School of Medicine in Maywood,
Illinois. Depending on their weight, study participants drank four or
five shots of vodka. Twenty minutes after reaching peak intoxication, their immune systems revved up. But when measured again,
at two hours and five hours after peak intoxication, their immune
systems had become less active than when sober.
The study by pulmonologist, critical care physician and
epidemiologist Majid Afshar, MD, MSCR, at the Loyola University Chicago Stritch School of Medicine and colleagues is
published online ahead of print in Alcohol, an international,
peer-reviewed journal. Many health risks of binge drinking are
sufficiently known. “But there is less awareness of alcohol’s
harmful effects in other areas, such as the immune system,”
said Elizabeth Kovacs, PhD, a co-author of the study and
director of Loyola’s Alcohol Research Program.
The National Institute on Alcohol Abuse and Alcoholism
defines ‘binge drinking’ as drinking enough to reach or exceed
a blood alcohol content of .08, the legal limit for driving. This
typically occurs after four drinks for women or five drinks for
men, consumed in two hours. One in six U.S. adults binge
drinks about four times a month, and binge drinking is more
common in young adults aged 18 to 34, according to the Centers for Disease Control and Prevention.
Less active
Two hours and five hours after peak intoxication, researchers
found the opposite effect: fewer circulating monocytes and
natural killer cells and higher levels of different types of cytokines that signal the immune system to become less active.
Dr. Afshar is planning a follow-up study of burn unit patients.
He will compare patients who had alcohol in their system
when they arrived with patients who were alcohol-free. He
will measure immune system markers from each group, and
compare their outcomes, including lung injury, organ failure
and death.
Majid Afshar, “Acute immunomodulatory effects of binge alcohol
ingestion”, in Alcohol, with co-authors Elizabeth Kovacs, PhD, of
Loyola and Stephanie Richards; Dean Mann, MD; Alan Cross, MD;
Gordon Smith, MPH; Giora Netzer, MD; and Jeffrey Hasday, MD, all
of the University of Maryland.
Ramping up
Dr. Afshar led the study while at the University of Maryland,
where he completed a fellowship before joining Loyola. The
study included eight women and seven men with a median
age of 27. Each volunteer drank enough shots of vodka – generally four or five – to meet the definition of binge drinking. Dr.
Afshar and colleagues took blood samples at twenty minutes,
two hours and five hours after peak intoxication because
these are times when intoxicated patients typically arrive at
trauma centres for treatment of alcohol-related injuries. The
blood samples showed that twenty minutes after peak intoxication, there was increased immune system activity. There
were higher levels of three types of white blood cells that are
key components of the immune system: leukocytes, monocytes and natural killer cells. There also were increased levels
of proteins called cytokines that signal the immune system to
ramp up.
Stonehenge trouble on stones. Licensed under CC BY-SA 2.0 via Wikimedia
Commons - http://commons.wikimedia.org/wiki/File:Stonehenge_trouble_
on_stones.jpg#mediaviewer/File:Stonehenge_trouble_on_stones.jpg
March 2015
IMMUUN
5
Carsten Linnemann wins Antoni van Leeuwenhoek prize 2015
Carsten Linnemann received this year’s Antoni van Leeuwenhoek prize on Monday, January 12. The prize is awarded annually
to an outstanding young researcher at the Netherlands Cancer Institute, in order to promote his or her career.
Linnemann’s work focuses on understanding the immune system
and stimulating it to destroy cancer cells. This type of cancer therapy, called immunotherapy, has recently known important breakthroughs. Linnemann, who is originally from Germany, obtained
his PhD cum laude in 2013 in the research group of Ton Schumacher.
His PhD research was funded by the Boehringer Ingelheim Fonds.
At the moment, he works as a postdoc in Schumacher’s group.
Schumacher calls Linnemann a ‘remarkably talented scientist’ who
in his young career has already made important contributions
to the development of cancer immunotherapy. During his PhD
research Linnemann focused on helping T cells to recognize cancer
cells. He did so by genetically modifying them to express new receptors, structures on the surface of T cells that can detect tumourspecific structures on the surface of cancer cells. Schumacher:
“Carsten showed that providing new receptors to T cells can also
cause problems. If the new receptors combine with receptors that
were already present, they will recognize unexpected structures as
‘hostile’, with unexpected results. He also found a solution for this.”
Enterprising
His work on T cells and receptor recognition earned Linnemann first
authorship on two papers in Nature Medicine. Last December he
6
IMMUUN
March 2015
was again first author of a paper in Nature Medicine. This time, Linnemann helped to prove that not just CD8+ T cells, but also CD4+
T cells are able to recognize cancer cells as ‘hostile’ and ‘dangerous’.
This makes these types of T cells into potential new targets for immunotherapy.
Schumacher goes on by calling Linnemann “very passionate,
enterprising, and an exceptional team player.” The enterprising part
shows from the fact that Schumacher and Linnemann are currently
founding a biotech company. The company will translate their
basal scientific work on T cells and receptors into T cell therapies for
cancer patients, in close collaboration with Schumacher’s group at
the NKI.
Surprised
“I was pretty surprised and very happy to hear that I’d receive this
prize”, says Linnemann. “I have worked at the NKI for seven years
now, and I have seen who won this prize before. They were all very
good scientists. I feel so honoured to now belong to this row.”
Linnemann plans to use the prize money of 6.000 euros on courses
teaching strategies how to best evolve academic research into
Biotech start-ups.
NEWS
Mirjam Mol pleads for
‘high risk, high reward’
funding
Unfortunately, the Netherlands have no big pharma
development left after the demise of MSD’s R&D in Oss.
Pivot Park director Mirjam Mol: “But we do have a lot of
knowledge and expertise that could be brought to the
point where it becomes attractive to big pharma. We
should have a financing model to accommodate every
step along this way. Yes, there is seed money, yes, there
is venture capital, but for the ‘high risk, high reward’
part in between, the so-called ‘valley of death’, there is
no solution. Policy is needed to tie the two loose ends
together to make a strong chain.”
AGENDA
26-27 maart 2015
Lunteren Symposium 2015
Immunity and Science Fiction: the next 50 years in Immunology
www.dutchsocietyimmunology.nl.
23 april 2015
Celkweek
Hogeschool van Arnhem en Nijmegen
1 dag van 18.00-21.00 uur
Locatie: Nijmegen
Kosten € 537,00
Informatie en aanmelding: www.hanlifesciences.nl of E: info.lifesciences@han.nl.
11-13 mei 2015
Jaarvergadering van de Association for Cancer Immunotherapy/CIMT
The right patient for the right therapy
Mainz, Duitsland
21 en 22 mei 2015
Workshop Analyse van Next Generation Sequencing (NGS) data
Hogeschool Leiden, CBD
Cursusprijs € 800,Inschrijven tot 7 mei 2015
Informatie & inschrijven: cbd@hsleiden.nl.
27 mei 2015
Workshop NGS in de microbiologie diagnostiek
Hogeschool Leiden, CBD
Cursusprijs € 480,Inschrijven vóór 15 april 2015
Informatie & inschrijving: cbd@hsleiden.nl
4 juni 2015
Scholingsdag Moleculaire Diagnostiek
Hogeschool Leiden, CBD
Cursusprijs: € 350,-.
Inschrijven vóór 23 april 2015
Informatie & inschrijven: cbd@hsleiden.nl
12 juni 2015
Masterclass Immunohistochemistry
Hogeschool Leiden, CBD
Cursusprijs € 480,-, bij inschrijven vóór 4 april 2015 € 435,-.
Informatie & inschrijven: cbd@hsleiden.nl
16 en 17 juni 2015
Workshop Primer en probes
Hogeschool Leiden, CBD
Cursusprijs € 740,-, bij inschrijven vóór 7 april € 675,-.
Informatie & inschrijven: cbd@hsleiden.nl.
Jesse
Kraal
In Immuun nr. 3
2014, on page 20
we erroneously
contributed three
photos to Jesse
Klaver: the photos
were made by
Jesse Kraal.
29 juni – 1 juli
Exploring Human Host-Microbiome Interactions in Health
and Disease
Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
6-9 september 2015
ECI2015
Jaarcongres European Congress of Immunology
www.eci-vienna2015.org
8 september 2015 (startdatum)
Labmanagement - Communicatie
Hogeschool van Arnhem en Nijmegen
Vier wekelijkse bijeenkomsten op dinsdag 9.00-13.00 uur
Locatie: Nijmegen
Kosten € 795,00
Informatie en aanmelding: www.hanlifesciences.nl of E: info.
lifesciences@han.nl
8 september 2015 (startdatum)
Labmanagement - Projectmanagement
Hogeschool van Arnhem en Nijmegen
Drie wekelijkse bijeenkomsten op dinsdag 14.00-18.00 uur
Locatie: Nijmegen
Kosten € 825,00
Informatie en aanmelding: www.hanlifesciences.nl of E: info.
lifesciences@han.nl
29 september 2015 (startdatum)
Labmanagement - Kwaliteitszorg
Hogeschool van Arnhem en Nijmegen
Vier bijeenkomsten op dinsdag 14.00-17.00 uur
Locatie: Nijmegen
Kosten € 795,00
Informatie en aanmelding: www.hanlifesciences.nl of E: info.
lifesciences@han.nl
1 en 8 oktober 2015
ELISA theorie; achtergronden en kwaliteitsaspecten
Cursusprijs € 720,- (bij inschrijven vóór 23 juli 2015 € 655,-)
Hogeschool Leiden, CBD
Informatie & inschrijving: cbd@hsleiden.nl
2, 16 oktober, 6, 20, 27 november en 4 december 2015
Pathologie
Hogeschool Leiden, CBD
Cursusprijs € 1.950,- (bij inschrijven vóór 24 juli 2015 € 1.775,-)
Informatie & inschrijving: cbd@hsleiden.nl
24 november 2015 (startdatum)
Immunologie
Hogeschool van Arnhem en Nijmegen
Vijf bijeenkomsten op dinsdag 18.00-21.00 uur
Locatie: Amsterdam (Sanquin)
Kosten € 552,00
Informatie en aanmelding: www.hanlifesciences.nl of E: info.
lifesciences@han.nl.
March 2015
IMMUUN
7
Cancer immunotherapy:
“Huge change of perspective”
Scientific progress is, if anything, usually slow. Or isn’t it? In the
case of cancer immunotherapy it certainly is not. The speed of
development over the last four to five years, from concept and
experiment to clinical reality, has been staggering. Professor Ton
Schumacher of Antoni van Leeuwenhoek hospital gives an overview
of what has been accomplished, what can be expected and which
challenges remain.
“In the USA, positive results have been reported with an
experimental treatment of metastasized melanoma. The
clinicians take T-cells from metastases, grow these in enormous
amounts in the lab and place these cells back into the patient.”
This quote on Tumour Infiltrating Lymphocyte (TIL) therapy
is derived from an interview with Ton Schumacher in the
publication ‘Immunologisch’ from 2011. Schumacher: “Back
then, we thought about immunotherapy for cancer treatment
as ‘possibly of value for treatment of melanoma’. Now we know
that it is a valuable treatment option for quite a number of
cancer types. Also, we think to have the insight for which types
of cancer this will be the case.”
“With the ‘major DNA damage’ cancer types you
can boost the existing immune reaction and
with the ‘minor DNA damage’ types you can use
gene therapy – with the hope that someday
both approaches meet in the middle”
Detection
One of the keywords related to progress in cancer
immunotherapy is detection. Schumacher: “Our immune
system is primarily aimed at targeting invaders such as viruses
and bacteria. The immune system recognizes these as notself because of their differing appearance. Most cancer types,
however, are not caused by viruses, so how can the immune
system recognize tumours? There are now many indications
that the immune system is particularly good at detecting
cancer types that are characterized by massive DNA damage.
8
IMMUUN
March 2015
Melanoma is an example, with DNA damage often caused by UV
radiation exposure.”
DNA damage causes proteins to be produced in cells that are
normally not there. “These deviations don’t go unnoticed by
the immune system. So with these types of cancer the immune
system is in many individual cases capable of a first essential
step: detection”, Schumacher concludes. His group is presently
developing technology to measure whether an individual
patient will develop an immune reaction against DNA damage
or not.
Phase III
Let us say the immune system has detected a tumour. Is it now
also capable of destroying these alien structures? In many cases
it isn’t, because a tumour deploys defence mechanisms that
block this immune reaction. Insight in how tumours achieve
that has grown in recent years. “Basically, the tumour cells
present proteins on their surface which activate a ‘brake’ on
immune cells”, says Schumacher.
By now, a number of therapeutic options has been developed
to overcome this inhibition. First of these is TIL therapy. In this
approach not only the number of T-cells to attack the tumour is
multiplied, the cells are also stimulated to be optimally active.
Schumacher: “In a clinical trial led by professor John Haanen
we have treated ten melanoma patients at the Antoni van
Leeuwenhoek with TIL therapy. Five of them clearly benefitted
from it. Two patients don’t even have any detectable tumour
left. These results are in line with other studies. What’s more,
with TIL therapy, resistance seems less of an issue than with, for
instance, drugs that block signal transduction routes.”
This first study is now followed up by a larger phase III
comparative multicentre study in which the Antoni van
Leeuwenhoek partners with Sanquin and centres in Great
Britain and Denmark. In this study the results of TIL treatment
of 150 patients will be compared to the results of patients
treated with Ipilimumab, a drug designed to inactivate CTLA-4,
one of the brakes on the immune system, allowing immune
cells to attack a tumour. “It will be the first ever phase III study to
compare TIL to a standard treatment”, says Schumacher.
Competitive field
In the meantime, the field of drugs such as Ipilimumab that
target brakes on the immune system, has become very
competitive. A number of clinical trials is running, aimed at
interfering with PD-1, a second brake in the immune system.
THEME: IMMUNOLOGY AND CANCER
These trials, which involve roughly halve the pharmaceutical
top ten companies, seem to lead to an even stronger clinical
response among an even higher percentage of patients than
Ipilimumab. Schumacher: “These clinical responses are not
solely limited to melanoma, but are now also seen in other types
of cancer, in particular types of cancer associated with extensive
DNA damage, such as lung cancer, bladder cancer, head and
neck cancer and other types.”
Furthermore, in addition to CTLA-4 and PD-1 there are many
other brakes on the immune system. There is much research
going on and there is still a lot to discover about these
blockers and their possible role in other types of cancer.
Many clinical studies are running which investigate
the role of new drugs or the potential of drugs used in
combination.
Patient specific
When brakes on the immune system are blocked,
this results in the activation of the entire immune
system - and hence with the chance of side effects
that resemble auto-immune disease. Schumacher
and his group aim to find out in which patients
the immune system is able to recognize a tumour
as not-self and why that is. Schumacher: “If we
know what an individual’s immune system can
recognize as not-self on cancer cells, we can
subsequently try to stimulate a specific immune
reaction. We could push the immune system’s
throttle, so to speak, to overcome the tumour’s
braking action.”
The DNA damage within a tumour is mostly
specific for the tumour of that individual patient.
This means that stimulation of an immune
response against this should also be patient
specific. In this way the treatment differs from the
classic pharmaceutical approach. “The approach is
new, but we know what process we need to develop.
Although presently we don’t know for certain whether
it will work. If successful, it will mean a major leap
forward. A completely tumour specific approach would
have the huge benefit of greatly reducing side-effects.
That would be unique in cancer treatment”, Schumacher
states.
Minor DNA damage
Up to this point, it was all about cancer types that are
characterized by large amounts of DNA damage. There are,
however, also cancer types in which only a minor of DNA
changes occurs, such as leukemia. In perspective: it ranges from
a factor ten to a hundred less DNA mutations. Schumacher: “The
consequence being that the immune system is in most cases
unable to detect these cancer types by itself, at least not by the
mutations they carry. Because of this, it is unsure as yet whether
immunotherapy will be effective for these cancer types.”
Ton Schumacher: “By now we know for certain that immunotherapy is
a valuable treatment option for quite a number of cancer types.
Theoretically, immunotherapy could provide future treatment for all
types of cancer.”
March 2015
IMMUUN
9
Changed perspective
It already means a huge shift in perspective as compared to
some years ago. “The world has changed”, Schumacher agrees.
“We now witness major pharmaceutical companies investing
massively in immunology based cancer drugs. We see how
clinicians in all kinds of oncology specialisations embrace
immune therapy. There is a lot of interaction with clinicians. All
in all, the field has changed dramatically.”
Among all this progress and optimism, one should bear the
present limitations in mind. “At this point, we cannot tell for
sure whether tumour specific immune stimulation is a feasible
option. Moreover, we shouldn’t forget that many patients still
have no response to the current immunotherapies”, Schumacher
reminds. And then there is the matter that in some cases there
is still only a temporary effect, before the tumour further evolves
and creates resistance against the immune attack. “There is a
lot of work to be done, clearly, but let’s not forget that we have
only started the widespread testing of immunotherapy in the
clinical setting a few years ago. The fact that resistance becomes
an issue shows how far we’ve come in short notice. That’s the
bright side of it.”
Leendert van der Ent
Photos Bureau Lorient Communicatie
Nederlandse samenvatting
Immunotherapie tegen kanker:
Het perspectief is snel verbeterd
A number of research groups, including that of Schumacher
therefore tries to change immune cells in such a way that
they become able to detect these ‘minor DNA damage’ types
of tumours too: “We know these tumour cells have specific
proteins on their surface which normally don’t cause an immune
reaction. Therefore we have to apply gene therapy to enable
immune cells to recognize the tumour.” T-cells are isolated and
activated in the lab. They are equipped with a receptor that
can detect whatever has to be detected. Finally, the treated
T-cells are reintroduced in the patient. Schumacher: “In the USA,
a number of clinical studies aimed at treating hematologic
malignancies with this approach have already been carried out.
Preliminary results are quite spectacular.”
This gives hope for the future. Schumacher further elaborates:
“If these preliminary results can be sustained, this would imply
that cancer immunotherapy can be applied to many types of
cancer, both for the ‘major DNA damage’ as well as the ‘minor
DNA damage’ tumour types. With the ‘major DNA damage’
cancer types you could boost the existing immune reaction and
with the ‘minor DNA damage’ types you could use gene therapy
– with hope that both approaches meet in the middle. This
would enable the ultimate goal: treatment of the entire array of
cancer types.”
10
IMMUUN
March 2015
In 2011 was immunotherapie tegen kanker nog grotendeels
theorie en belofte. Professor Ton Schumacher van het Antoni
van Leeuwenhoek: “Inmiddels weten we dat immunotherapie een waardevolle behandelingsoptie is bij verschillende
soorten kanker. Ook het inzicht in de dynamiek van kanker
in relatie tot het immuunsysteem is enorm gegroeid.” Bij
kankertypen die gekarakteriseerd worden door een grote
hoeveelheid DNA-schade, zoals melanoom en longkanker,
herkent het immuunsysteem de tumor vaak als ‘vreemd’. Dat
is nog niet hetzelfde als vernietiging, want tumoren hebben
een verdedigingssysteem dat de immuunreactie afremt. Er
zijn verschillende benaderingen om het immuunsysteem
zodanig te versterken dat het over kan gaan tot de vernietiging van de tumor. Bij kankertypen die relatief weinig DNAschade aanrichten, zoals leukemie, herkent het immuunsysteem de kanker waarschijnlijk in de meeste gevallen niet.
Gentherapie kan ervoor zorgen dat het immuunsysteem
de kanker wel herkent. Als de voorlopige resultaten op dit
gebied kunnen worden bevestigd, dan biedt dit de hoop dat
op termijn voor vrijwel alle soorten kanker immunotherapie
beschikbaar kan komen. Hoewel er nog een lange weg te
gaan is, hebben de spectaculaire resultaten die de laatste jaren bereikt zijn al voor grote veranderingen gezorgd. De ‘big
farma’ investeert nu veel in de ontwikkeling van op immunologie gebaseerde kankermedicijnen en clinici verwelkomen
immunotherapie als nieuwe behandelingsoptie.
THEME: IMMUNOLOGY AND CANCER
A world’s first:
Preventive vaccine against
hereditary colorectal cancer
Hoogerbrugge and De
Vries: “What if we could
boost the immune system
of people with Lynch
syndrome before cancer
has got the chance to
develop?”
(photo Bureau Lorient
Communicatie)
Jolanda de Vries and Nicoline Hoogerbrugge have vaccinated a group of twenty volunteers with Lynch syndrome
against Lynch-related (hereditary) cancer at Radboudumc. They have mainly assessed the safety of the vaccine. This
preventive vaccine against hereditary cancer should provide people with Lynch syndrome a more effective protection
against the cancer for which they have a predisposition. The clinical trial is a first step in preventive vaccination
against hereditary cancer.
The Lynch syndrome stands for a hereditary mismatch in the
repair genes. It causes a life time risk of up to 70% of developing
colorectal cancer, against 5% in the general population.
Furthermore, in Lynch syndrome cancer develops at a relatively
young age. The immune system eradicates cancer cells
continuously, especially in people with Lynch syndrome since
their cancer cells and precursors thereof express antigens
foreign to the immune system. Unfortunately, the balance
between immune attack and tumour cell growth can be
disturbed and tumours can grow.
Jolanda de Vries (PhD) is professor at the Department of Tumor
Immunology at the Radboud Institute for Molecular Life
Sciences (RIMLS). She explains: “The body is very careful with
DNA. DNA is built up in two matching strings. Normally, there is
a meticulous check on DNA that is copied. A DNA-repair system
exerts it’s function when copying has not been perfect and
repairs DNA-mismatches. When mismatches are not repaired,
there is a higher probability of developing cancer precursor cells,
derailed non-self cells, which can develop into cancer. That is
what happens in people with Lynch syndrome: the repair system
does not function flawlessly.”
No therapy available
In Lynch syndrome patients, aberrant cells expressing incorrect
proteins result from incorrect DNA translation. A distinguishing
feature of these cells is that they present fragments of the
incorrect protein, neo-peptides, on their surface. The immune
March 2015
IMMUUN
11
Who is Jolanda de Vries?
Jolanda de Vries (PhD) is professor at the Department
of Tumour Immunology at the Radboud Institute for
Molecular Life Sciences (RIMLS). She was among the
pioneers to translate dendritic cell biology into clinical
applications. The first clinical phase I/II studies in which
patients were vaccinated with DCs loaded with tumorspecific peptides were initiated in 1997. She also developed
a novel immuno-monitoring assay that is highly predictive
for extended survival after vaccination with DCs. Her
primary scientific interest continues along the line of
DC-immunotherapy and in particular the migration and
imaging of DC.
system can recognise these neo-peptides as non-self. It is
activated and destroys these cells before a tumour is formed.
The immune system of people with Lynch syndrome works as
it should and is activated. Their immune system is even capable
of fighting the malignant cells. But in many Lynch individuals,
the unusually large flood of non-self cells as compared to other
people, overpowers their immune system and cancer develops.
Nicoline Hoogerbrugge, MD, PhD, is internist-cancer geneticist
and professor in Hereditary Cancer at the department of Human
Genetics at the Radboudumc: “There is no therapy to prevent
Lynch syndrome related cancer. Typically, we see adenoma/
polyps with an increasingly malignant nature occur in people
with the syndrome. Our standard procedure is to track people
with this syndrome from the age of 25 to offer them regular
surveillance for adenomas. By performing colonoscopy and
removing the adenomas we try to prevent colorectal cancer in
an early stage.”
Dendritic cells turn the patient’s own T-cells
against neo-peptides on (pre)cancer cells
Prevention
De Vries is specialized in the development of vaccines to boost
the immune system in people with cancer. De Vries: “We witness
cases in which immune therapy enables the immune system
to beat cancer. Theoretically it is far more effective to boost
the immune system before cancer has developed, when the
patient’s immune system is still intact, than to try to beat an
already existing tumour. But normally, preventive vaccines
are not an option because you don’t know who is going to
develop what kind of cancer and when. Hereditary cancer is
the exception to this rule: with for instance Lynch syndrome
you know exactly who runs a very high risk of getting colorectal
cancer at an early age.”
Hoogerbrugge: “Therefore Jolanda and I thought that it would
be better to boost the immune system of these people before
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IMMUUN
March 2015
De Vries: “The
immune system
reacts positively to
the vaccine and we
don’t notice an autoimmune reaction.”
cancer has got the chance to develop. What we typically
observed in Lynch related colorectal cancer lesions was the
presence of high numbers of immune cells compared to
colorectal cancer lesions from non-hereditary cancer patients.
Therefore we concluded that Lynch related cancers are
immunogenic. So we thought: if only we could strengthen the
immune reaction of these people in time, this would possibly
enable them to withstand malignant cells.”
Building on experience
Contrary to the situation with non-hereditary cancer, with
Lynch syndrome it can be predicted which neo-antigenic
peptides are presented on the surface of the cancer cells. De
Vries: “This enables prevention in the same way as we normally
perform immunotherapy against existing cancer, when there
already is a response against tumour antigens. The vaccine
consists of patients’ own dendritic cells loaded with neopeptides. The dendritic cells thus stimulate the patient’s own
T-cells against these peptides; we don’t generate T-cells outside
the body. In general, when you vaccinate against a mutation,
this works far better than when you vaccinate against proteins
Who is Nicoline Hoogerbrugge?
Nicoline Hoogerbrugge, MD, PhD is internist-cancer geneticist
and professor in Hereditary Cancer at the department of
Human Genetics at the Radboudumc. She is an adjunct
clinical professor in hereditary cancer at Haukeland University
in Bergen, Norway since 2011. Her clinical research is
multidisciplinary in familial and hereditary colorectal cancer.
Her expertise ranges from recognition of those at high risk
for hereditary cancer, early diagnosis, innovation of care,
new immunological treatment and cost efficacy studies. Her
fundamental research is focused on identification and clinical
characterization of novel genetic causes for colorectal and
gastric cancer at adult age and in childhood.
THEME: IMMUNOLOGY AND CANCER
“There is no therapy
to prevent the Lynch
syndrome cancer”,
Hoogerbrugge states.
that are also present on healthy cells. In this way, we hope to
enable the T-cells to destroy the cancer. Or, alternatively in the
case of preventive use, to destroy the precursors of tumour cells,
or even to evoke an immune memory response, enabling the
immune system to immediately recognise and destroy cancer
precursor cells once they appear. In a therapeutic as well as in a
preventive setting, we hope to alert the immune system against
the threat, in order to stop the malignant process.”
De Vries applies this kind of therapy in melanoma for eighteen
years already. “We can build on this experience. The preventive
vaccine benefits from progress made in cancer immunotherapy.
We now make dendritic cells from precursor cells in the blood,
which takes nine days. It has recently become possible to load
natural dendritic cells from the blood with neo-peptides, which
saves time and subsequently money. Moreover, in patients
with cancer this is also more effective, so why not when
applied preventively? The development is still too early and too
specialised to perform a multicentre study yet, but this new
method is more suited for such a study as it is technologically
somewhat less demanding.”
It is important to note that this preventive vaccination is totally
unrelated to for instance mass vaccination against HPV. De Vries
emphasises: “It is an individual approach, very laborious and
costly, targeted at a limited group of people who run a high risk
of developing cancer”.
Trial
Trials aimed at prevention face very high demands, as people
who are not ill may not be exposed to any kind of risk.
Hoogerbrugge and De Vries were able to establish this, got
approval for a trial and gathered a group of twenty still healthy
volunteers with the Lynch syndrome to further prove the safety
of their vaccine. This safety aspect especially regards autoimmune reaction. The vaccine rouses the immune reaction
against the derailing intestinal cells before they have gotten
the chance to develop into cancer cells. “It is important, that at
the same time the immune balance stays intact; the immune
reaction shouldn’t change in an auto-immune reaction.
The volunteers were vaccinated from spring 2014 onward. By
now, all twenty volunteers have been vaccinated. “The first
results are encouraging”, says Hoogerbrugge, “Although it is still
too early to establish whether the immune system can indeed
be boosted to prevent the development of colorectal cancer. ”
“What we can say”, says De Vries, “is that the immune system
reacts positively and that we don’t notice an auto-immune
reaction. But it will take longer to draw conclusions on cancer
prevention. We will only know that it worked, when people with
Lynch syndrome develop colorectal cancer later than expected
or even not at all.” If all goes well, it would also open perspectives
for other types of hereditary cancer. Hoogerbrugge: “In that case
we hope to administer preventive vaccines for other types of
hereditary cancer as well. But for the moment we concentrate
on this type of tumour. To find answers to the questions
regarding the Lynch syndrome is difficult enough as it is.”
Leendert van der Ent
Photos Lagro Fotografie
Nederlandse samenvatting
Eerste preventieve vaccinatie
tegen erfelijke kanker
Het Radboudumc heeft twintig vrijwilligers met Lynch
syndroom, dat een kans van 70% op het ontwikkelen
van erfelijke darmkanker geeft, gevaccineerd om kanker
te voorkomen. Het afweersysteem is niet altijd krachtig
genoeg om kankercellen, ontspoorde cellen, helemaal
op te ruimen. Bij mensen met het Lynch syndroom, die
drager zijn van een erfelijke fout in één van de DNAreparatiegenen, ontstaan vaker “foute” cellen. Nicoline
Hoogerbrugge, hoogleraar Erfelijke Kanker in het
Radboudumc: “Voor het Lynch syndroom bestaat nog
geen therapie. Mensen met dit syndroom screenen we
vanaf vijfentwintigjarige leeftijd regelmatig op adenomen,
het voorstadium van darmkanker. Door adenomen te
verwijderen proberen we het ontstaan van darmkanker
vroegtijdig te voorkomen.”
Het preventieve vaccin tegen erfelijke darmkanker moet
hen een nog effectievere bescherming bieden. Hoogleraar
Translationele Tumorimmunologie in het Radboudumc
Jolanda de Vries ontwikkelde dit vaccin: “De vrijwilligers
die in ons onderzoek het vaccin krijgen, hebben nog
geen kanker en we hopen met het vaccin het ontstaan
van darmkanker te voorkomen.” Het brengt de afweer
tegen ontsporende darmcellen op gang voordat deze zich
ontwikkelen tot kankercellen. Daarbij moet wel een balans
bewaard blijven; afweer mag niet omslaan in een autoimmuunreactie. De eerste resultaten zijn hoopgevend.
“Inmiddels zijn alle mensen gevaccineerd”, aldus De Vries.
“We zien een goede reactie van het afweersysteem. Het
geeft hoop dat het vaccin werkt. Zekerheid hebben we pas
na langere tijd, als deze mensen veel later dan gebruikelijk
of zelfs helemaal geen darmkanker ontwikkelen.”
March 2015
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Circulating Tumour Cells:
A key to cancer detection, drug
Leon Terstappen brought the Circulating Tumour Cell capture technology CellSearch to the clinic. It allows patient monitoring
and early detection of metastases instead of only risk-profile based prognosis. Further development of the technology, for instance
in the European CTC-TRAP project, enables cell-specific information to direct personalized, targeted therapy at an early stage of
(recurrent) cancer.
Only ten percent of cancer patients die from their primary
tumour. Ninety percent succumb as a consequence of
metastases caused by cells that have detached from the primary
tumour. These Circulating Tumour Cells (CTC) move through
the blood. Most of these cells are destroyed in the liver or by the
immune system, but some escape to form new malignancies/
metastases. If only these CTC could be detected.
That was the completely new hypothesis behind the research
started by professor Leon Terstappen MD, PhD in the USA
in 1995. Terstappen indeed found a way to detect CTC. This
was the start of a hundred million dollar research project and
the development of Immunicon Corporation’s CellSearch
technology. The technology was taken over by Johnson &
Johnson in 2008, after it had been FDA cleared and brought to
the clinic in 2004. CellSearch is now deployed for patient
monitoring in about four hundred hospitals
worldwide, one of which is the Erasmus Medical
Centre in Rotterdam.
Extremely rare
Leon Terstappen: “In drug development we
wish to make the step from stating that a drug
responds to a percentage of tumour cells with
a certain receptor to the percentage of patients
who actually respond to the therapy.”
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IMMUUN
March 2015
“Normally, you will need tumour cells to
make an assessment of which therapies
will be the most effective to arrive at a
personalised approach”, says Terstappen.
“But it is hard to take a biopsy from
tumour metastasis. It is of course
possible to store cells from the primary
tumour after surgery for later use, but
these may no longer be representative
of the tumour at the time therapy is
needed. Cancer cells mutate, change
their phenotype and genotype; this is
exactly what makes these cells resistant
to therapy. The most critical aspect in
cancers is their heterogeneity and constant
change. Cells from the primary tumour
may therefore not be representative for the
metastasis. You need up-to-date tumour
information.”
So how do you know what to look for?
Terstappen: “My hypothesis was based on the
fact that epithelial cells don’t belong in the blood.
When you find those, they have to come from a
THEME: IMMUNOLOGY AND CANCER
development and treatment
carcinoma. To find these, you take an immunologic marker,
antibodies that target epithelial cells to label them. You
connect the marker to small magnetic particles. Subsequently
it becomes possible to extract the magnetically labelled CTC
from the blood with a magnet.” This is the simplified story of
the CellSearch technology. The scientific version was published
in the New England Journal of Medicine and in Clinical Cancer
Research in 2004.
To find CTCs is much harder than suggested above, given the
fact that CTCs in the blood are extremely rare. To find CTCs,
the procedure starts by using 7.5 millilitres of blood. In a first
step, billions of red blood cells and millions of white cells are
separated from the rest. What remains are the CTC among now
hundreds to thousands of white blood cells. The CTC can be
found with fluorescently labelled antibodies to distinguish them
from the remaining white blood cells. Terstappen underlines:
“Immunology is vital to this technology. Everything revolves
around the antigens present on the CTC, antibodies to these
immunologic markers are labelled with magnetic particles to
select them from the blood and fluorescent markers to enable
their identification under the microscope.”
Prognosis to observation
The first hypothesis was proven: yes, these cells can be detected.
The second hypothesis was, that detection of these cells point
out the need for further treatment. This was also clinically
proven from 2004 onward, first with breast cancer and later
with prostate and colon cancer: finding CTC means a worse
prognosis for the patient. Terstappen: “When CTC are still
present after three weeks of therapy, it means the therapy hasn’t
worked and something else has to be undertaken to battle the
cancer.”
Conventionally, once the primary tumour is removed from
cancer patients, they are treated according to a prognostic risk
profile that is based on the findings around the time of surgery
and the characteristics of the tumour at that time. Terstappen:
“The CellSearch technology enables the step from therapy based
on risk for recurrence to the actual observation of the presence
of micro or macro metastasis.”
Same cells, different receptors
Since 2004, the number of scientific publications on the
CellSearch principle has skyrocketed to 10,000 to 30,000 at
the moment. These articles focus on further development and
deployment of the approach in new applications. Terstappen:
Everything revolves around the antigens
present on the CTC
“Apart from the diagnostic monitoring application – to establish
whether recent therapy has been effective – there is another
major field of application. Once you have detected the CTC, it is
also attractive to find out to what substances they are sensitive.
A lot of studies therefore involve pharma trials in which
CellSearch is used to determine whether a new target is able to
bind to the CTC.”
Unfortunately, this is also more complex than previously
perceived. Terstappen: “The biological Herceptin, for instance,
is approved for aiming at the Herceptin receptor on the cells
of the primary tumour. When the CTC, the tumour cells in the
blood, are investigated at the individual cell level, it appears that
there is a large variation of the expression of the receptor on the
tumour cells implying that the therapy can only be effective on
a portion of the tumour cells. This is vital information that was
not taken into account before.”
“This might mean that a patient may need additional drugs that
can attack the other tumour cells in order for the therapy to be
Who is Leon Terstappen?
Leon Terstappen received his Medical Degree from the
University of Groningen in 1983 and his PhD from the
Department of Applied Physics of Twente University
in 1988. He worked on stem cell characterization as a
post-doctoral fellow and in various research positions
at the research institute of Becton Dickinson, San Jose,
CA, USA. He joined Immunicon Corporation (now J&J) in
1994 to pioneer the detection of tumour cells in blood of
cancer patients as Chief Scientific Officer and Senior Vice
President of Research and Development. He developed
the CellSearch-technology for which the Prix Galien was
received in 2009. In 2007 he was appointed Professor of
Medical Cell Biophysics at the University of Twente and
at the UT MIRA-Institute for Technical Medicine and
Biomedical Technology. The International Society for
Analytical Cytology (ISAC) awarded him the ‘Max Fulwyler
Award for Innovative Excellence’ for his research into cell
detection and analysis in 2012. Terstappen has about fifty
patents to his name and is involved in the start-up Vycap.
March 2015
IMMUUN
15
effective. Good future biologicals will need to target a relevant
combination of receptors”, Terstappen concludes.
Immunology is vital to this technology
More detail
How unfortunate this complexity may be, it is highly relevant
information for drug development as well as further patient
treatment in the clinic. Terstappen: “Traditionally, tumour cells
are characterized as -, +, ++ or +++ for the presence of potential
therapy targets. The development of CTC detection is aimed
at a much more detailed and quantitative description of the
tumour profile, at the genetic expression as well as the protein
expression level. Various receptors occur in a certain measure
on the CTCs. This receptor-profile, which informs on the per cell
expression of different receptors, should define treatment. It
will for instance make clear whether targets for new treatments
should be aimed at the oestrogen receptor or the androgen
receptor regardless of the origin of the tumour.”
More knowledge and more detail result in a better hit
chance for new targets – the most pressing challenge for the
pharmaceutical industry. This is the philosophy behind the
European precompetitive Public Private Partnership Innovative
Medicines Initiative (IMI) CANCER-ID, in which Terstappen coleads a 14 million euro project. Terstappen: “We wish to validate
technologies for blood-based biomarkers to determine the
absence or presence of drug targets and assess the response to
treatment. We will be able to establish which therapy is the most
effective for the individual patients. This program will enable
Immune defense live at work
Terstappen: “What you see here is immune defense live
at work: a first image of a Circulating Tumour Cell that
we detected, with T-lymphocytes attached to it. It would
be a great leap forward if we understand what actually
happens. The immune system obviously recognizes the CTC
as foe and tries to destroy it. In cancer, this ultimately fails.
The challenge is to multiply the destructive power of the
T-cells. We can make is visible. I hope that researchers are
willing to take this mechanism from there and determine
what actually happens. For instance: what do T-cells
recognize in these tumour cells? Why can they in many
cases destroy cancer cells, but in some cases not? Are there
not enough T-cells? Are they not powerful enough? How
can they be strengthened? How often does it occur that
one or more T-cells are attached to CTC? What happens
next – destruction or failure? What are the differences
between individuals? This has never been systematically
investigated.”
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IMMUUN
March 2015
pharmaceutical companies to deploy the best technology in their
studies for new drugs and accelerate the process of getting the
drugs only to the patients that will benefit from it.
Therapy?
Apart from supporting diagnosis and enabling new drugs
research, the merits of the CTC detection technology to provide
a therapy are now under investigation in the six million euro
European Research project CTC Circulating Tumour Cells
TheRapeutic Apheresis (CTC-TRAP). Terstappen explains: “This
new project aims at real time liquid biopsy in patients suspected
of metastasis. Instead of taking only milliliters of blood, this
project involves the patient’s total blood volume. We strive to
filter the blood in a way comparable to dialysis. In half an hour,
all the patient’s blood passes the filter, leaving the CTC behind.”
Filtering five liters of blood takes the technology to a whole
new level as compared to analysis of a couple of millilitres.
Terstappen: “All the CTC have to be detected for analysis in order
to get all the info needed for tailored treatment for individual
patients. The challenge is huge. Once CTC-TRAP is developed,
it also has to be validated. Validation of the technology in lung
cancer is the aim of CANCER-ID another upcoming European
project which involves 26 centers throughout Europe. The
ultimate goal is to personalize therapy on the basis of tumour
cells available during the entire disease process. In this way you
can adapt therapy according to new information. CTC contain
this information, so we need to get as much out of it as possible.
Hopefully we will at some point be able to treat patients based
on their CTC phenotype and genotype.”
Leendert van der Ent
Photos Bureau Lorient Communicatie
THEME: IMMUNOLOGY AND CANCER
Treatment of cancer patients with immunotherapy looks
promising. Sanquin Reagents notices this too. There is a
strong interest in her technologies to monitor antigen-specific
T cell populations in clinical trials with new medication.
Relevant epitope iden�fica�on Neo-­‐epitopes Vaccine targets Proof of Mechanism Treatment op�misa�on Candidate selec�on Monitoring Cytotoxic T cell popula�ons Immunotherapy & Immune monitoring tools Powered by patent families WO 2006/080837, WO 2010/060439, WO 2012/076708 Monitoring Immunotherapy
Immunotherapy focuses on stimulating cytotoxic T cells to
eliminate cancer cells. How do you know which target is
important and do T cells respond to this? Sanquin has extensive
expertise in immunology and blood cells and has, among others,
developed technology aimed at both identifying relevant targets
and phenotyping a wide range of antigen-specific cytotoxic T
cells (CTL).
however feasible to analyse up to 10 antigens simultaneously,
and we are happy to discuss licensing options with interested
parties. We have already been contacted by several Dutch and
international biotechnology and pharmaceutical companies.”
Immune monitoring CTL populations:
Proof of mechanism
“In contrast to other assays, our assays allow you to discriminate
whether an activation observed is non-specific or is related to
anticipated antigen-specific effects of treatment. In addition,
we can determine whether the antigen-specific population
consists of predominantly effector, effector memory, central
memory or naïve T cells.” Astrid Visser explains. “This allows
researchers to verify at an early stage in a clinical trial whether
their therapy does what it is expected to do. It gives insight into
the effects of an experimental therapy and can be used in the
process of establishing a proof of mechanism.”
Improved epitope selection
One of our proprietary toolsets improves the selection of
relevant T-cell epitopes.
When you know which proteins are relevant in a tumour, in
silico programs can identify candidate epitope peptides that are
likely to bind MHC complexes. We found that even though some
of these programs work well, they are not suitable for ranking
the best candidates. Sanquin’s peptide-MHC binding assay
selects and confirms the best candidates presented by the MHC
(eliminating about 20% of predicted candidate epitopes that do
not actually bind), and also provides a ranking that is well linked
to in-vivo relevance (leading to more optimal immunotherapy
vaccines).
As servicetest or for licensing
Sanquin Reagents offers this patented technology, developed
together with the Netherlands Cancer Institute, as one of
its services in the field of immunotherapy. “Antigen-specific
immune monitoring is fairly complicated; execution requires a
certain level of expertise. For most experienced FACS users it is
This article was made
possible by Sanquin Reagents.
Contact: Astrid Visser,
Business Development Manager,
a.visser@sanquin.nl, +31 (0) 20 512 32 40,
http://www.sanquin.nl/reagents
March 2015
IMMUUN
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Lia van der Hoek wins Immuno
Lia van der Hoek (AMC) has won the Immuno Valley Award 2014 for her pitch ‘Virus discovery, fast, sensitive and cheap’ at
the Immuno Valley Annual Conference 2014. Van der Hoek, associate professor at the Academic Medical Center, developed
a technology that enables fast identification of viruses. She already discovered around fifteen new viruses. “In virus discovery
things go so fast that in five years time all human viruses may have been identified.”
Viruses are curious things. They’re generally not considered
living organisms, since they’re just strains of DNA or RNA
in a protein coat (and in some cases an envelope of lipids).
They replicate inside the living cells of other organisms, from
animal, humans and plants to microorganisms. So far, about
5,000 human and animal viruses have been described in detail.
But there are many more species and virologist Lia van der
Hoek has developed a technology to discover these. That is
easier said than done, since it is difficult to separate the DNA or
RNA of a virus from the host’s DNA and RNA. Only a fraction of
a clinical sample is relevant for sequencing, but how to purify
the fraction to focus on?
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March 2015
A nice hobby
Lia van der Hoek got her PhD in 1998, working on HIV-1 in the
digestive tract. “In 2001, I started to develop my own method
that would make it possible to discover viruses in a fast and
sensitive manner”, she says. At the time it was sort of a hobby
project, executed next to her regular work. A very successful
hobby project that is, since it resulted in 2003 in the VIDISCA
(Virus Discovery cDNA-AFLP) technology. Her first shot at
a sample containing an unidentified virus was a hit: she
discovered a new human coronavirus (HCoV-NL63) with her
brand new technology. For the next five years, she shifted her
VIRUS DISCOVERY
Valley Award 2014
Winning pitch at Immuno Valley
Annual Conference
Lia van der Hoek (AMC) presented her pitch ‘Virus
Discovery, fast sensitive and cheap’ at the Immuno Valley
Annual Conference. There were six presenters, who all did
a great job, according to jury members Peter van Dijken
(TNO), Mark Offerhaus (Micreos) and William Weldon
(Elanco Animal Health). Van der Hoek however won the
Immuno Valley Award 2014. The jury was impressed with
her work, her presentation and the practical application of
her idea.
Van der Hoek received the award and a cheque of 2500
euros. Van der Hoek: “I also got the opportunity to
participate in a two day ‘pitch training’. The training taught
me a lot on how to present an idea and captivate the
attention of possible partners. I can also put these skills to
good use in the classroom!”
Van der Hoek praises Immuno Valley for building bridges
between scientists and businesses, in human and animal
health. “Immuno Valley makes it possible for me to come
into contact with people whom I would otherwise
not meet, thus creating relevant opportunities for
partnerships. I hope the Immuno Valley Award will be
another incentive for partners to explore possibilities for
cooperation that are mutually beneficial.”
More information on Immuno Valley at www.immunovalley.nl
attention towards this novel virus until 2008 when she took up
further improvement of the virus discovery method. She did so
by combining VIDISCA with Next Generation Sequencing and
novel purification techniques. Next Generation Sequencing
provides ten thousands to millions of sequences per sample,
an extremely powerful tool which is today introduced in many
genomics projects.
cheaper, costs less computing power, is faster and enables
analyzing more samples.” For this achievement she received
the Immuno Valley Award 2014 (see box).
A new virus a new pathogen?
Van der Hoek is continuously improving her method. “I’m always
on the lookout for ways to make VIDISCA more sensitive and
faster”, she says. But the method is already a success. So far,
it has enabled Van der Hoek to discover around fifteen new
viruses, eight of which have been published. What happens
after discovery? “Then we always determine whether an
infection with the novel virus is associated with disease. We
make a diagnostic assay and find out whether it presents
itself more often in sick patients than in a healthy controls. If
this association is confirmed the virus is a serious pathogen
candidate. The next step is to fulfill the Koch’s postulates:
culture the virus from a sick animal or human, applying pure
virus in an animal model and isolate the virus from these guinea
pigs. If the animals get the disease then the causal relationship
between infection and disease has been validated”.
Modern times
The revolutionary Next Generation Sequencing technology has
facilitated identification of unknown viruses at a speed that was
out of reach some years back. “In virus discovery things happen
so fast it’s almost unbelievable”, Van der Hoek says. “I can’t
even exclude the possibility that five years from now all human
viruses will be identified. After that, of course, we still have a
massive challenge in linking these viruses to diseases.”
Alinda Wolthuis
Photo Immuno Valley
Nederlandse samenvatting
Lia van der Hoek winnaar Immuno
Eliminate the enemy
Valley Award 2014
One of the main competitors for virus discovery is ribosomal
RNA that is massively present in clinical material and
competes with sequencing of viral genomes. The purification
technique that Van der Hoek introduced enables separation
of the relevant part from the irrelevant part of a sample.
By applying special elongation and non-elongation
oligonucleotide primers ribosomal RNA is removed from a
sample. “The fact that we remove a large part of the irrelevant
material means that we have less sequencing to do: it’s
De pitch ‘Snel, gevoelig en goedkoop virussen ontdekken’ tijdens
de Immuno Valley jaarconferentie 2014 leverde Lia van der
Hoek de Immuno Valley Award op. Van der Hoek, Universitair
Hoofddocent op het AMC, ontwikkelde een technologie die een
snelle identificatie van virussen binnen bereik brengt. Ze ontdekte
verschillende nieuwe virussen in de afgelopen jaren. “In virusdiscovery gaan de ontwikkelingen zo snel dat binnen vijf jaar alle
humane virussen geïdentificeerd zouden kunnen zijn.”
March 2015
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Onvermoede relatie tussen schiz
Bij het ontstaan van schizofrenie spelen erfelijke factoren een grote
rol. ‘Dat weten we uit tweelingonderzoek’, zegt Eske Derks die zich
als hoogleraar Genetica vooral richt op psychiatrische aandoeningen. ‘Heeft een eeneiige tweelingbroer of -zus schizofrenie, dan is de
kans vijftig procent dat de ander het ook krijgt. Bij de overige broers
of zussen daalt die kans naar zo’n tien procent, maar dat is nog altijd
aanzienlijk hoger dan gemiddeld.’
Ook omgevingsfactoren spelen een rol. Kinderen die bijvoorbeeld in de winter of het vroege voorjaar worden geboren, hebben een licht verhoogde kans op schizofrenie. ‘Dat zou te maken
kunnen hebben met een grotere kans op infecties in het najaar’,
zegt Derks. ‘Infecties tijdens de zwangerschapsfase hebben
mogelijk een negatief effect op de (hersen)ontwikkeling van de
ongeboren vrucht.’
Genetische kwetsbaarheid
Er zijn meer aanwijzingen dat infecties, immuniteit en afweer
iets te maken kunnen hebben met schizofrenie, en andersom.
Derks: ‘Mensen met schizofrenie zijn vatbaarder voor infecties.
Niet alleen voordat de diagnose schizofrenie wordt gesteld,
maar ook daarna. Recent is duidelijk geworden dat medicatie die
de afweer dempt bij een deel van de schizofreniepatiënten een
goed effect heeft op de ziekte. Als aspirine wordt toegevoegd
aan de gebruikelijke anti-psychotica verbetert de toestand van
sommige patiënten.’
Derks en haar collega’s onderzochten daarom of er een genetische overlap bestaat tussen schizofrenie en immunologische
aandoeningen. Met andere woorden: zijn genen of genetische
gebieden die bij schizofrenie betrokken zijn, óók actief bij het
ontstaan van immunologische aandoeningen, zoals diabetes
type 1, de ziekte van Crohn en reumatoïde artritis (RA)? Voor dit
onderzoek bekeek Derks de genetische variatie in grote patiëntengroepen.
‘Er zijn nog maar weinig genen bekend die de kans op schizofrenie vergroten’, zegt Derks, ‘maar met statistisch onderzoek
kunnen we ook naar wat grotere stukken DNA, ofwel genetische
regio’s, kijken waarvan we vermoeden dat dergelijke genen zich
daar moeten bevinden. Die aanpak hebben we gevolgd voor vier
patiëntengroepen: mensen met schizofrenie en mensen met de
ziekte van Crohn, diabetes type 1 en reumatoïde artritis.’
‘Beruchte’ regio
In de analyse voor schizofrenie springt bijvoorbeeld een ‘beruchte’ regio op chromosoom 5 in het oog. Daar liggen diverse
genen die al eerder met schizofrenie in verband zijn gebracht,
zoals ACSL6 en NEUROG1. Maar – en dat maakt het interessant – diezelfde regio bevat ook veel genen die een rol spelen in
de afweer. Er zitten bijvoorbeeld enkele genen die coderen voor
interleukines, dat zijn signaalstoffen die delen van de afweer
aansturen. Op chromosoom 6 ligt ook zo’n gebied met zowel
immunologische genen (Humane Leukocyt Antigenen, HLA) als
genen die een grotere kans op schizofrenie geven.’
Derks: ‘Ons onderzoek, gepubliceerd in Schizophrenia Research,
wijst uit dat er een duidelijke genetische overlap bestaat tussen
schizofrenie enerzijds en de drie immuunziekten anderzijds.
Vrij snel na onze publicatie verscheen een artikel in Nature met
nog grotere patiëntengroepen, maar met een vergelijkbare
conclusie. De volgende fase van het onderzoek zal zich moeten
richten op de biologische signaalroutes van de aandoeningen,
op de moleculaire onderbouwing van de ziektes. We moeten
nu de stap maken van statistische verbanden naar biologische
verklaringen.’
Bijsturen
Dergelijk onderzoek vergt een lange adem en kan zowel vanuit
de psychiatrie als de immunologie worden gevoed. Met interessante perspectieven, denkt Derks. ‘Stel dat we inderdaad kunnen
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IMMUUN
March 2015
Science across borders
ofrenie en afweerstoornissen
aantonen dat ontstekingen en bepaalde variaties in de afweer
de kans op schizofrenie vergroten. Dan kunnen we mensen met
een hoog risico op schizofrenie misschien wel preventief met
bepaalde ontstekingsremmers gaan behandelen. Juist omdat
schizofrenie sterk genetisch is bepaald, kunnen we potentiële
patiënten relatief eenvoudig opsporen. Iemand beter maken die
schizofrenie heeft, is moeilijk. Preventie door tijdig bij te sturen,
is bij deze ziekte een optie die veel meer kansen biedt.’
Pieter Lomans
English summary
Remarkable correlation between immunology and schizophrenia
Genes that make people vulnerable for schizophrenia are partly also involved in immunological diseases such as
type 1 diabetes, Crohn’s disease and rheumatoid arthritis. The next step is to find out what this partial overlap of
the schizophrenia related genes with the immunological disorder related genes tells us.
Hereditary factors play a vital role in the occurrence of schizophrenia. “We know that from research with twins’, says professor
in Genetics Eske Derks, who mainly focuses at psychiatric diseases. ‘When an identical twin brother or sister has schizophrenia,
the risk is fifty percent that the other also gets this disease. Among the other brothers and sisters this chance drops to about ten
percent, which is still far higher than average.”
Environmental factors also play a role. For instance, children born in winter or early spring run a slightly higher risk of getting
schizophrenia. “This could have to do with a higher risk of infections during the autumn”, says Derks. ‘Infections during pregnancy
possibly have a negative effect on the brain development of the unborn child.’
Genetic vulnerability
There are more indications that infections and immunity on one side and schizophrenia on the other side are interrelated. Derks:
“Schizophrenia patients are more susceptible to infections. This not only goes before the diagnosis schizophrenia is made, but
also after. Recently it has become clear that immune moderating medication has a dampening effect on the manifestation of
schizophrenia among a part of the patients.
Notorious region
In the analysis of schizophrenia a ‘notorious’ region on chromosome 5 stands out. Derks: “Various genes are located there which
have been identified as related to schizophrenia, such as ACSL6 and NEUROG1. But – and that is what makes it interesting – this
very same region also contains many genes that play a role in the immune system. There are for instance some genes which code
for interleukins, signal substances which can activate part of the immune system. On chromosome 6 there is also a location with
‘immunological’ genes (Human Leukocyte Antigens, HLA) as well as genes that cause a higher risk of schizophrenia.”
Derks proceeds: “Our research results, published in Schizophrenia Research, point out that there is a clear genetic overlap
between schizophrenia on the one side and type 1 diabetes, Crohn’s and rheumatoid arthritis on the other. Already quite quickly
after our publication was published, an article was published in Nature on the basis of even larger patient groups, with a
comparable conclusion. The next phase of the research will have to focus on the biological signal routes of the diseases, on their
molecular basis and process. We now have to make the step from statistic correlations to biologic explanations.”
Pieter Lomans
This article was previously published in AMC Magazine December 2014 / January 2015
March 2015
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Cancer research at the Pivot Park
Pivot Park is the science park in Oss aiming at bridging life sciences
and technology. The park has come a long way since its official
opening in 2012. Thanks to its roots in MSD and predecessor Organon
- a company that cherished immunology as a spearhead – cancer
immunology research is very well represented on the site. Companies
such as BioNovion and Acerta Pharma are living proof of this.
Activities on the Pivot Park are more or less equally divided into
one third new product development, one third pharmaceutical
contract research and manufacturing and one third enabling
services. About two thirds of the new product development
involves immunology research. A considerable part of this is
dedicated to cancer research, with links to the NKI, academic
medical centers and large pharmaceutical companies.
Chief Scientific Officer Andrea van Elsas of BioNovion, a pioneer
at the park: “The Netherlands is home to a disproportionately
large, globally recognised expertise in immunology- not in the
least in cancer immunotherapy. Organon was the corporate
figurehead in this respect, a position that could be maintained
under Schering-Plough and MSD.” Pivot Park emerged from major
MSD reorganizations and former MSD-experts started their own
spin-outs at the park, just like BioNovion. “It is no surprise that
immunology is a major research field here”, Van Elsas concludes.
There is a large variety of research and development activities.
These range from lead discovery, development, compound
manufacturing from lab scale up to pilot plant production and early
stage clinical trials to dossier submission. This covers the middle of
the pharmaceutical value chain, the bridge between academia and
big pharma. There are many connections between the companies
on the site. Mol: “We actively stimulate collaboration through our
open access labs and community events.”
Mol sees the transformation of Pivot Park into a lively campus as
a dot on the horizon. “The shared entrance with MSD and Aspen
necessitates closed gates. A separate entrance would enable
evolution towards an open campus, with the look and feel of a
community with its own restaurant and an outdoor café.”
Highly valuable equipment
“Pivot Park is ready for its next step, to become a vibrant life
sciences community”, Van Eenennaam, Chief Operating Officer
of BioNovion agrees. BioNovion started three years ago in an
incubator setting and moved last December to a larger facility
of its own, also at the Pivot Park. Van Eenennaam: “Thanks to
equipment and labs that were already in place, we could start
experimenting from the start. We have our own facilities now,
but still do use the park’s infrastructure.”
Mirjam Mol: “We offer the R&D
infrastructure of large companies to SMEs”
Dot on the horizon
“After two and a half years, Pivot Park now houses some 35
companies with about 350 employees”, says park director
Mirjam Mol. “Fifty percent of the available capacity is now
rented out. Pivot Park has state-of-the-art core facilities and
infrastructure for pharmaceutical research and development,
with special start-up packages, ranging from simple glassware
to advanced equipment such as HPLC systems and parallel
synthesis equipment. But the park also hosts manufacturing
capabilities, has the Pivot Park Screening Center for high
throughput screening and provides all-in lab services, from
handling complex gases to waste management. Companies
can buy a subscription to lab equipment or bring their
samples to have them analysed or screened. We offer the R&D
infrastructure of large companies to Small and Mediumsized
Enterprises (SMEs).”
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IMMUUN
March 2015
Number one on the wish list: to open the
gates to welcome visitors to the campus.
(Photo Pivot Park)
IMMUNOLOGY AND CANCER
Acerta Pharma joined Pivot Park more recently. Executive vice
president discovery Allard Kaptein: “It is a huge benefit to be
able to use the highly valuable equipment of the Screening
Center. Another opportunity was that as a result of the latest
MSD reorganization in July 2014 we could hire experienced
researchers, who could immediately contribute to our activities.”
Acerta Pharma is an R&D company focused on oncology and
auto-immune disease. Kaptein: “It’s all about activated immune
cells gone out of control, which can lead to auto-immune disease
as well as rapid malignant cell growth. Our specialization is the
development of covalent binding drugs, which attach permanently
to target proteins. Once the drug is bound its presence in the
circulation is no longer needed. While still being effective on the
target, it lowers the risk of off-target adverse effects.”
Hans van Eenennaam: “Pivot Park
is now ready for this next step, to
further grow into a vibrant life
sciences community”
From idea to clinical trial
BioNovion builds on academic knowledge of antibody
application against the immune checkpoint protein CTLA-4
and on Organon’s research into therapeutic antibodies against
another immune checkpoint protein, PD-1 (see the interview
Other companies on the Pivot Park
involved in cancer immunology research:
• Contract research company NTRC also has its own line
of research in oncology and immunology.
• Synaffix is active in the field of Antibody Drug
Conjugates (ADC).
• Glycostem is dedicated to innovative (stem) cell therapy
against diseases, including cancer.
• Intervention in the process of degenerative diseases such
as diabetes and cancer is the aim of Lead Pharma.
with Ton Schumacher). This Organon work, started in 2004,
eventually led to Pembrolizumab as the first anti PD-1 drug
approved by the FDA – Merck’s Keytruda.
Van Eenennaam: “Our place in the value chain is to bring
research ideas towards clinical trials. This proof of concept
work is based on fundamental understanding of tumour
immmunotherapy. Our technology platform with its Organonroots enables us to identify and produce antibodies which
activate or inhibit immune cells in order to optimally mobilize
them against cancer – or other immune relate diseases.”
BioNovion CSO Andrea van Elsas: “We do not produce just
antibodies, we make ready-for-testing, functional, producible
and safe antibodies. This is a big difference, that enables the
vital step towards a marketable product.”
Allard Kaptein: “It is a huge benefit to be able
to use the highly valuable equipment of the
Screening Center”
BioNovion strives to combine these competences with
academic knowledge and therefore seeks collaboration with
academic researchers who dispose of a biologic model system.
Van Eenennaam: “This combined knowledge can actually get
new drugs to the clinic.Take for instance our collaboration
with Jannie Borst at the NKI, who brings in twenty years of
knowledge of CD27. This has, with the support of TI Pharma,
now led to a new product concept.” Another collaboration
involves professor Kenneth Anderson at the Dana-Farber Cancer
Institute in Boston, regarding treatment of multiple myeloma.
In addition to growth by successful start-ups, Pivot Park also
manages to attract parties from outside. Last year’s decision
by the clinical trial services multinational Quintiles to join Pivot
Park meant a breakthrough to the international scene. Mol is
confident that a transformation towards an open campus will
persuade more companies to join. “This would bring eighty to
ninety percent occupation within reach.”
Leendert van der Ent
This article was made possible by Pivot Park and Brabantse
Ontwikkelings Maatschappij (BOM), www.bom.nl.
March 2015
IMMUUN
23
Hidde Ploegh
Breakthroughs at the intersection
“The single most important thing is passion”, says immunologist Hidde Ploegh. Passion for research brought him to the other
side of the Atlantic. Already as a graduate student he worked at Jack Strominger’s lab at Harvard. Today, he heads the Ploegh
Lab at the Whitehead Institute for Biomedical Research. He studies the various tactics that viruses deploy to evade our immune
responses and the ways in which our immune system distinguishes friend from foe.“In my lab I’m surrounded by (bio)chemists,
cell biologists and engineers. It’s a good place to be.”
His career has linked him to a number of respected institutions:
Harvard University, the University of Cologne, The Netherlands
Cancer Institute (NKI), the VU University Amsterdam, Harvard
Medical School, The Whitehead Institute for Biomedical
Research and Massachusetts Institute of Technology. Since
2005 Ploegh is on the faculty at the Whitehead Institute
and MIT. Here he is in his element. “It’s a curiosity-driven
environment and I’m at liberty to follow my research instincts to
my heart’s content.”
Fascination for the MHC
Whereas there may have been changes in his employers, Ploegh
has been consistent in his research object of choice: the major
histocompatibility complex, MHC. His first achievement was
cloning a cDNA for a major MHC antigen. He continued to study
The joy of teaching
“I like to teach. I get the impression that in the Netherlands
many professors are reluctant to enter a classroom, they
prefer doing their own thing in the lab. At MIT we all
are expected to teach, I myself just finished a 24 x 2 hour
course and I had tremendous fun in the process. We have
a fascinating profession and I enjoy talking about it. I don’t
make use of powerpoints, I use old-fashioned chalk and
blackboard, because that makes it easier for students to
follow the pace of exposition. I also make sure to tell things
they can’t find in their textbooks - and then test it in the
exam.”
synthesis and trafficking of MHC products, but broadened the
scope by studying pathogens that hide by incapacitating MHC
products and the cellular protein degradation pathways that
provide them with their peptide antigens. At the Whitehead
Institute, Ploegh studies how viruses evade immune responses,
and the ways in which the immune system distinguishes friend
from foe. The Ploegh Lab reported new mechanisms by which
dendritic cells detect the presence of antigens and instruct the
immune response, using Class II MHC-eGFP knockin mice and
live cell imaging. Ploegh also helped to elucidate how products
of the major histocompatibility complex are assembled and are
delivered to the right destination to help an immune response
kick in: herpes viruses such as HCMV evade the immune system
by selective destruction of Class I MHC products.
New labeling methods
Nobel Prizes
“The number of immunologists to have won a Nobel Prize,
is surprisingly large. That can be explained by the fact that
discoveries in immunology are very recognizable. The same
goes for genetics, by the way.”
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March 2015
The Ploegh Lab applies chemistry-based strategies to illuminate
aspects of protein quality control. “At the Whitehead I find
myself surrounded by really good chemists and specialists
from other disciplines. That suits me like a glove: working at
the intersection of disciplines can lead to real breakthroughs.
I myself probably know more chemistry than the average
immunologist and I almost certainly know a lot more about
immunology than the average chemist. That enables me to
define interesting research subjects. My colleagues are always
willing to lend me a hand to solve technical problems.”
of disciplines
Extremely charismatic, phenomenal classes
“I was inspired by Jon van Rood, an extremely charismatic
immunologist who was well ahead of his time. I also credit
Jan Drenth, biochemist at Rijksuniversiteit Groningen. His
classes were phenomenal: he was a credit to biochemistry
as well as eloquent, and he had a marvelous sense of
humor.”
Dutch immunology stands out
“The Netherlands stand out in immunology. Every single
Dutch university boasts a credible effort in immunology
and the Dutch Society for Immunology is a large and
vibrant community. There is a downside to this: objective
peer review of research results is more difficult because all
Dutch immunologists know each other. They should look
abroad for peers.”
So far, Ploegh and his coworkers have emphasized the
generation of chemical tools to study proteasome activity and
the roles of lysosomal and ubiquitin-specific proteases. A recent
innovation is the generation of cloned mice with lymphocytes
specific for pathogens such as Toxoplasma, influenza and herpes
viruses, using the technique of somatic cell nuclear transfer.
As one of the keynote speakers at he NVVI Winter School
2014, Ploegh impressed the audience with his lecture on new
labeling methods that enable labeling any protein in mice,
thus disclosing chains of events that remained invisible until
now. “With our new method, we can see whether immune
cells can find a tumour and if so, what they do to it. We can
follow this process in time. This might help us to determine why
immunotherapy is successful in some cases and unsuccessful
in other cases. Developing this method required a combination
of immunological, chemical and biochemical knowledge, all of
which is present at the Whitehead.”
Breaking new ground
Ploegh, who is a contributor to over five hundred papers, always
opts for fundamental research. “Applied research is just not my
cup of tea. I’m better at exploring new grounds, to do what has
not been done before and to develop new technologies, new
approaches and new tools. I’m happy to leave applied science to
others. I encourage people to build on our results and use our
discoveries to their own ends. I regard it as a compliment.”
He is horrified by the current drive for valorisation. “I don’t
understand the attraction of it. In the Netherlands it is
presented as an American example to follow, whereas in reality
in the States such a concept or philosophy doesn’t exist. Let’s
be clear on this: fundamental research is the source from
which spring most if not all medical applications such as new
chemotherapeutics or biologicals. If the fundamental research
is sound, applications will follow. One shouldn’t be forced into
‘valorisation’.” So far, all of his ideas have landed somewhere.
“Sometimes in places I hadn’t expected, but that’s all the more
fun.”
The second immunology revolution
“In the fifties, immunology was responsible for the
elimination of nearly all infectious diseases in children.
Now, immunology is about to revolutionize healthcare
for the second time: cancer immunology will prove to be
a breakthrough. In malignant melanoma, forty percent
of patients can be treated successfully with antibodies.
Soon this treatment option will become available for other
cancers as well.”
March 2015
IMMUUN
25
PhD students have mastered this and then graduate, they
unfortunately leave the club.”
Level playing field
Over the years, Ploegh has seen come and go many coworkers.
A significant number of them are now leading scientists in
the Netherlands, for instance Sjaak Neefjes, Ton Schumacher,
Huib Ovaa, Peter Peters, Madelon Maurice, Marianne Boes and
Hermen Overkleeft. “It’s great to see how they’ve developed
their own line of research and become leading scientists in their
own fields. I like to think that the work they did with me has
contributed to their current achievements, has helped them to
identify new opportunities and to challenge themselves. I like to
keep in touch, too.”
Cross-Atlantic relations are therefore warm and frequent, as
is emphasized by his part-time appointment as professor in
cellular protein chemistry at Utrecht University. How does
Ploegh regard the current scientific climate in Europe? A decade
ago, he stated in an interview that the climate in the US was
more ‘vibrant and lively’ than in most places in Europe and
praised himself lucky to be in the Boston academic climate, with
its ample resources and intellectual firepower. That may hold
truth to some degree even today, he says, but the differences
have become less apparent since he first set foot in America
in 1992. “There has been a leveling of the playing field on both
sides of the Atlantic. Email and social media make information
exchange quick and simple. Universities have access to all top
publications. That has promoted interaction across the Atlantic
- and stimulated science on both sides.”
Alinda Wolthuis
Photos Bureau Lorient Communicatie
“With our new method we can see whether immune cells can find a tumour and,
if so, what they do to it. We can follow the process in time. This might help us to
determine why immunotherapy is successful in some cases and unsuccessful in
other cases.”
The explorer Ploegh likes breaking new ground. He does not
have a long-term strategy and he doesn’t know what he’ll be
doing five years from now. Ploegh: “There is stability in the
sense that there is longterm financing for my program, but
that’s about it. Flexibility is key at the Whitehead. That is both
my wish as it is the institute’s policy: I do not employ staff nor
analytical researchers on a permanent basis. PhD students enlist
for the MIT graduate program, not for a defined project. They
can’t get a permanent position with us. There is a downside
to this flexibility, of course. Along with the graduating PhD
students, their specialized knowledge is at risk of disappearing.
Also, certain technologies, such as the generation of cloned
mice, requires expertise that takes time to master. But once
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March 2015
Passie voor vernieuwing
“Het allerbelangrijkste is passie”, zegt immunoloog Hidde
Ploegh. Passie voor onderzoek bracht hem naar de andere kant
van de Atlantische oceaan, waar hij leiding geeft aan het Ploegh
Lab bij het Whitehead Institute for Biomedical Research. Hij
bestudeert de taktieken waarmee virussen een immuunrespons
weten te omzeilen en de manier waarop het immuunsysteem
vriend en vijand uit elkaar houdt. Zijn focus ligt op fundamenteel
onderzoek. Dat hij in het Whitehead voornamelijk nietimmunologen om zich heen heeft, bevalt hem uitstekend: “Voor
vernieuwing moet je op het kruispunt van disciplines zijn.”
Cancer Vaccine Tracking project:
Translating immunology to the clinic
The CTMM Cancer Vaccine Tracking project has brought expertise of chemistry, pharmacology, imaging and immunology
together. Thanks to this multidisciplinary project, a therapeutic vaccine against cervical and vulvar cancer now approaches
market introduction. “The project plays a vital role in bringing ‘molecule’ to ‘man’, bringing scientific knowledge to the clinic”,
prof.dr. Ferry Ossendorp, LUMC and prof.dr. Kees Melief, CSO at ISA Pharmaceuticals in Leiden conclude.
Some decades ago it was discovered that T-cells can recognize
virus infected cells and tumours via the presentation of foreign
proteins presented as short peptides on the cell surface.
This knowledge opened the way towards immunotherapy
against cancer. “We have proceeded on that”, says prof. dr.
Ferry Ossendorp of the Leiden UMC, principal investigator of
the CTMM Cancer Vaccine Tracking project. “On the basis of
the immune system’s ability to recognize foreign peptides we
developed an immunotherapy based on therapeutic peptide
vaccination against virus-induced tumours, in particular against
the viral onco-proteins of the Human Papilloma Virus that
can cause cervical and vulvar malignancies and head and neck
cancer.”
The right peptides
The heart of the matter is, to teach the immune system to elicit
a strong response against the right proteins. Some researchers
choose to work with short peptides, that are loaded directly
onto all kinds of cells by Human Leukocyte Antigen (HLA)
molecules. “This introduces the risk of an unbalanced immune
response. We therefore choose to work with long peptides
Kees Melief and Ferry
Ossendorp: “We hope to
learn how the synthetic
long peptide therapies
behave in-vivo, which
would help us to direct
our research with
optimal efficiency”
(Photo Bureau Lorient
Communicatie)
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IMMUUN
March 2015
instead. Long peptides require a processing step, which only
dendritic cells can accomplish. To stimulate a T-cell response
with a low dosage of long peptides in the proper stimulatory
context of a DC is a safer and more efficacious solution. No
active drug is introduced, but a pro-drug that is metabolized to
an active drug in the DC”, says Melief.
Ossendorp: “Furthermore, long peptides don’t cause HLA
matching problems and can thus be indiscriminately used in
all patients. Nine of the long peptides cover the E6 oncogene
protein, four cover the E7 oncogene protein. The vaccine is
injected subcutaneously with a small needle to the skin of the
upper arm. The vaccinated peptides gain easy access to the
many local dendritic cells (DCs). These move to lymph nodes,
where they activate both types of T-cells, CD4 helper cells and
CD8 killer cells. Subsequently, the activated T-cells go out to turn
against the E6 and E7 proteins specifically expressed by the (pre-)
malignant tissues.
Preliminary clinical results
ISA Pharmaceutical sponsors a clinical trial with 48 patients in
nine centres in the Benelux. Clinical results show that synthetic
Project partners:
CTMM
-
-
-
-
-
Leiden University (Organic Chemistry group Hermen
Overkleeft - fluorophore labeling, TLR ligand conjugate,
Synthetic Large Peptide development)
Leiden UMC (Tumor immunology, In vivo imaging.
GMP Facility: SLP vaccine production, fluorophore
peptide production. Hospital: clinical trial)
Utrecht University (nanoparticle formulation
development)
Percuros BV (imaging)
ISA Pharmaceuticals BV (vaccine development, clinical
trials)
Over the past seven years, the Center for Translational
Molecular Medicine (CTMM) established a highly effective
infrastructure for public-private partnerships, translating
science into better healthcare. Newly developed molecular
technologies in the field of diagnostics and imaging make
early diagnosis and patient-tailored treatment possible
for oncologic, cardiovascular and neurodegenerative
conditions, as well as for infectious and auto-immune
diseases. CTMM and TI Pharma are preparing to merge
into one organization to collaborate on public-private
healthcare innovation.
long peptide immunotherapy is safe and effective in premalignant indications. Melief: “In combination with standard
chemotherapy it looks favourable in patients with late stage
cancer. In the pre-clinical as well as the clinical model, chemo
plus long peptides works better than checkpoint blocking plus
long peptides. We show that chemotherapy leads to depletion
of immunosuppressive cells, resulting in a synergistic effect with
long peptide treatment.”
“In this trial, the long peptides are directly connected to
immune stimulating molecules: Toll Like Receptor (TLR) ligand
conjugates. In pre-clinical models this new approach behaves
more bioactive than the unconjugated long peptide version,
because it targets the peptide to the DC and simultaneously
activates them. Ossendorp explains: “It thus stimulates
important DC functions more effectively and consequently also
induces a stronger T-cell response at lower doses.”
The multidisciplinary approach of the CTMM Cancer
Vaccine Tracking project, combining imaging, synthesis and
immunology, brought this progress about. In a previous project,
TI Pharma supported the all-important intellectual property
positioning and drug development. CTMM subsequently
sponsored the step from molecule to the clinic. Vital support,
according to Melief: “Thanks to this, large patient groups could
eventually benefit from these specific immunotherapeutics.
That’s how it was intended. It is good to see that it really works
out that way.” Ossendorp: “The project has brought it within our
reach to offer the best possible immunotherapy to the patient.”
Imaging gives insight
The Cancer Vaccine Tracking project focuses on in-vivo imaging
of the therapeutic from the injection site to the draining lymph
nodes, in order to offer the researchers maximum insight in the
immunization process. Prof.dr. Hermen Overkleeft’s organic
chemistry group connected a near infrared fluorophore label
to one of the long peptides. This, together with Percuros’
imaging technology, enables non-radioactive imaging deep
into the tissue. Melief: “The synthetic nature of this project’s
Synthetic Long Peptides (SLP®) and the in-vivo imaging aspects
enable replacement of the traditional empirical approaches in
research by step-by-step design, in which pharmaco kinetics
and pharmaco dynamics are taken into account, including time,
place, formulation and dosage aspects.”
This year, a trial with healthy test persons will start at the Center
for Human Drug Research (CHDR) to test the imaging results of
the fluorophore-labelled SLP. Also a new formulation is tested,
where the emulsion is replaced by a nanoparticle encapsulation
slow release alternative. This delivery technology was developed
by the Utrecht University Pharmacology Group of prof.dr. Wim
Hennink. “We hope to learn how the long peptides behave invivo, which would help us to direct our research with optimal
efficiency”, says Ossendorp.
Next generation
Apart from the labelling and formulation, the T-cell response
to the vaccine itself is also improved. A clinical trial with new
generation synthetic long peptides will start shortly. Melief:
Nederlandse samenvatting
Het CTMM-project Cancer Vaccine Tracking brengt
chemische, beeldvormende, farmacologische en
immunologische expertise samen om een therapeutisch
vaccin tegen baarmoederhals- en schaamlipkanker naar
de markt te brengen. De ontwikkelde beeldvormende
mogelijkheden verschaffen inzicht dat in het vaccinonderzoek de stap van trial en error naar meer gerichte en
geplande ontwikkeling mogelijk maakt. “Het project is een
belangrijk voorbeeld van hoe je van ‘molecuul’ naar ‘mens’
gaat en wetenschappelijke kennis in de kliniek brengt”,
concluderen prof. dr. Ferry Ossendorp, LUMC en prof. dr.
Kees Melief, CSO van ISA Pharmaceuticals in Leiden.
Dit artikel is mogelijk gemaakt door CTMM: www.ctmm.nl
March 2015
IMMUUN
29
Lunteren Symposium
Immunity and Science Fiction:
The next fifty years of
On the 26th and 27th of March 2015, the Lunteren Symposium will take place. It is dedicated to the 50th anniversary of the
Dutch Society for Immunology (NVVI). ‘Immunology research in the next fifty years’ was chosen as a fitting team for this spring
meeting. What immunological challenges lie ahead? Nationally and internationally renowned speakers comment on this.
In the opening session Hans Clevers (Hubrecht Institute,
Utrecht) will kick off with a presentation on ‘Stem cells: Dr Jekyll
or Mr Hyde?’ Clevers is the President of the Royal Netherlands
Academy of Arts and Sciences (KNAW), professor in molecular
genetics and one of the world’s leading researchers on stem cells
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March 2015
and their potential for regenerative therapy.
Clevers was the first to identify stem cells in the intestine.
He discovered similarities between the normal renewal of
cells in the intestine and the onset of colon cancer. His group
has since been able to grow mini-organs or ‘organoids’ from
immunology research
individual stem cells of the intestine. These epithelial organoid
cultures are genetically and phenotypically extremely stable,
allowing transplantation of the cultured offspring of a single
stem cell, as well as allowing disease modelling by growing
organoids directly from diseased patient tissues. These exciting
developments have great potential to repair genetic defects in
stem cells of patient tissues.
The second speaker, Nienke Vrisekoop (University Medical
Center Utrecht), is inspired by immune cell dynamics,
specifically T-cell dynamics in time and space. Immune cells
are the most mobile cells in the body. They can ‘patrol’ through
tissues and reach inflammatory sites quickly. To study T-cell
dynamics in living mice she uses intravital 2-photon microscopy.
Vrisekoop also studies the relationship between the binding
strength of the T-cell receptor - the unique receptor which
T-cells use to recognize their specific antigen - to presented
foreign antigen and the strength of self-peptide Major
Histocompatibility Complex (MHC) reactivity. Mathematical
modelling will enable to estimate the true immune cell contact
times and will enable to predict how the observed contacts add
up over time and space.
T-cells
Christopher Love (Associate Professor of Chemical Engineering
at the Massachusetts Institute of Technology (MIT) and Ton
Schumacher (professor of Immune Technology at the Leiden
University Medical Center, with his lab at the Netherlands
Cancer Institute (NKI) Amsterdam) are the speakers of the
session on T-cells. They will reveal novel approaches to dissect
heterogeneity within T-cell populations and tell how they
use this to manipulate the molecular processes underlying
differentiation of and immune recognition by T lymphocytes.
The main aim of Love’s research is to understand how
heterogeneity in cell populations affects their collective
behaviours as a system. Research in The Love Lab combines
ideas from materials science and interfacial chemistry to enable
new micro- and nanotechnologies for studying the biology
of complex cell collections in a quantitative manner. The lab’s
researchers have developed new processes for analysing large
numbers of individual living cells quantitatively and dynamically,
with the use of high-throughput screening of monoclonal
antibodies, micro tools for profiling immune responses and
microfluidic systems for live cell imaging. The resulting profiles
will enable understanding of for example the precise cellular
signatures that characterize an immune response to one disease
state or another.
Schumacher aims to design and test novel concepts for
adoptive immunotherapy of cancer. To this end he designs
novel technologies that can be used to examine and modify
antigen-specific T-cell immunity. He also uses these tools to
unravel and manipulate the molecular processes underlying
immune recognition by T lymphocytes. The lab has developed
methods to trace cell fate at the single cell level, using genetic
barcodes. Another line of research involves mapping of all
tumour-specific mutations within human cancer lesions, using
exome sequencing, which could serve as regression antigens
in patients. The link between cancer genomics and T-cell
immunology may suggest novel ways to harness the T-cell
repertoire in human disease.
B-cells
Hergen Spits (Academic Medical Center Amsterdam) and
Michael Reth (scientific director of the BIOSS Centre for
Biological Signalling Studies, Freiburg, and full professor in
Molecular Immunology at the University of Freiburg) represent
two research extremes in the field of B-cell biology. This field
is about the discovery of therapeutic antibodies for clinical
use and the development of techniques for a profound study
of signalling mechanisms in B-cells, respectively. Apart from
professor of Immunology, Spits is also co-founder of AIMM
Therapeutics, a company that aims to discover therapeutic
antibodies for the treatment of cancer and infectious diseases.
This company’s approach is based on genetic programming
of human memory B-cells into long living plasmablasts. The
method provides a tool to immortalize B-cells, enabling the
rapid generation of high-affinity human monoclonal antibodies
without the need to use extensive molecular engineering
techniques.
Another strategy involves the development of bispecific
antibodies to create a covalently linked IgG antibody
heterodimer.
Reth’s research line focuses on the Nano-scale organization of
the B-cell receptor (BCR) on resting and activated B-cells. The
exact organization of proteins in the membrane of living cells is
still poorly understood. By combining novel assays to detect the
proximity of two target proteins and through state-of-the-art
super-resolution microscopy techniques, Freiburg researchers
have been able to investigate the structure, organization and
dynamics of the BCR and its interaction with co-receptors.
The studies suggest that many membrane proteins are not
freely diffusing monomers, but rather multicomponent protein
complexes pre-organized in nano-size protein islands.
March 2015
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31
Extracellular vesicles
The evening lecture will be dedicated to extracellular vesicles
(EVs) or, by their former name, exosomes. Clotilde Thery is
Research Director and group lead at the Institute Curie in Paris.
Already in 1998 she was fascinated by EVs. These are formed in
the endocytic compartment and subsequently secreted outside
the cell. Although EVs can be produced by almost all cells, Thery
is especially interested in those produced by dendritic cells (DCs)
and tumour cells. By using extensive proteomic analysis she has
studied the composition of EVs and provided a detailed map of
the proteins selectively targeted to these vesicles. Using state-ofthe-art cell biological approaches, the intracellular mechanism of
EV formation and secretion has been analysed, which will provide
novel therapeutic options in the fight against cancer.
High resolution
In the session on high resolution, Daniel Davis (director
of research in the Manchester Collaborative Centre for
Inflammation Research (CCIR), professor at the University
of Manchester), and Paul Parren (Senior Vice President and
Scientific Director of Genmab in Utrecht and professor at the
University of Southern Denmark (Odense) will demonstrate
what is experimentally possible with new imaging techniques
that dive into the nano-range. Davis specializes in visualizing
cell-cell interactions, including the immunological synapse, a
special organization of molecules between immune cells that
is important for the activation of T-cells and the killing of virally
infected cells or tumour cells. Scientists at Davis’ lab discovered
that long, thin connections, ‘membrane nanotubes’, developed
between cells. Cells use these to communicate at a distance.
Using high resolution microscopy, Davis’ team demonstrated
that immune cells transport genetic material, small RNA
molecules, through these membrane nanotubes to cancer cells.
Thereby they inhibit the proliferation of these cells. Davis will
focus on the possibilities and limitations of high- and superresolution microscopy to demonstrate which questions can be
addressed with this promising new approach.
Parren is highly interested in the biology of antibodies and
in particular how these immune molecules can be applied
successfully for immunotherapy. To understand how antibodies
behave inside the body, Parren and his team explore the
structure of antibodies and how they exert their effector
function. He uses high resolution mass spectrometry to
study the molecular details of an antibody, including the
sugar structures. He will discuss various novel high resolution
approaches that enable investigating in great detail both the
structure and function of proteins in general and antibodies in
particular.
Neuronal control
“Influencing the immune system with your brain, wouldn’t
that be great?”, asked both Peter Pickkers and Paul-Peter
Tak themselves a number of years ago. Since then they have
investigated this idea and exploited their findings in the clinic
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March 2015
for the benefit of patients. In the session on neuronal control
they will demonstrate that there is considerable interplay
between the autonomic nervous system and the immune
system: both the parasympathetic (via the vagus nerve) and the
sympathetic nervous system exert regulatory functions on the
immune response. The so-called ‘cholinergic anti-inflammatory
pathway’ may represent a novel therapeutic modality to limit
inflammation in various conditions.
As professor of Experimental Intensive Care Medicine at
the Radboud University Medical Center Nijmegen, Pickkers
investigates the immune system during sepsis. In his
presentation he will focus on the parasympathetic cholinergic
anti-inflammatory pathway and will discuss interactions
between the sympathetic nervous system and the immune
system. He will demonstrate that through practicing
techniques developed by ‘iceman’ Wim Hof it is possible to
activate the sympathetic nervous system at will and that this
results in suppression of immune responses. Paul-Peter Tak
is Senior Vice President / Head of the Immuno Inflammation
Unit at GlaxoSmithKline (Stevenage, UK) and professor of
Rheumatology at the University of Cambridge. He has a strong
background in successfully developing novel treatment options
for patients with rheumatoid arthritis and other chronic
inflammatory diseases, in particular vagus nerve stimulation
as a new bioelectronics anti-inflammatory approach. In
his presentation he will not only present the results of this
revolutionary work, but also expand upon the potential use of
bio-electronics in the treatment of other diseases in the near
future.
Advanced imaging
The closing lecture ‘Intravital immunology: seeing T-cells make
decisions’ will be delivered by dr. Thorsten Mempel, principal
investigator at the Center for Immunology and Inflammatory
Diseases, Massachusetts General Hospital in Charlestown
MA, and associate professor of Medicine at Harvard Medical
School in Boston MA. Mempel’s lab seeks to understand how
the function of T-cells is regulated through their interaction
with other cells, structural tissue components and soluble
mediators that they encounter in tissues. For this purpose
the lab researchers use advanced imaging techniques such
as multiphoton intravital microscopy (MP-IVM). This allows
them not only to observe the migration of immune cells in their
physiological tissue context in living humanized mice, but also
to monitor the activities of various signaling pathways and how
these are regulated by intercellular contacts.
NVVI Symposium Lunteren, 2015, March 26-27
Congrescentrum De Werelt, Lunteren, The Netherlands
Thursday March 26
Friday March 27
11.00
8.15
Welcome and Introduction
‘Meet-the-speaker’ breakfast sessions
Session 1: Perspective: In vitro vs In vivo
Chair: Annemiek van Spriel
Session 4: High resolution
Chair: Martijn Nolte
11.15
Hans Clevers (Utrecht, The Netherlands)
9.00
Dan Davis (Manchester, UK)
12.00
Nienke Vrisekoop (Utrecht, The Netherlands)
9.45
Paul Parren (Utrecht, The Netherlands)
12.45
Lunch
10.30
Coffee
Session 2: T cells
Chair: Debbie van Baarle
Session 5: Neuronal control
Chair: Sander Tas
13.45
Christopher Love (Cambridge, USA)
11.00
Peter Pickkers (Nijmegen, The Netherlands)
14.30
Ton Schumacher (Amsterdam, The Netherlands)
11.45
Paul-Peter Tak (Stevenage, UK)
15.15
Tea
12.30
Lunch
Session 3: B Cells
Chair: Rudi Hendriks
Closing lecture
Chair: Maaike Ressing
13.15
16.00
Hergen Spits (Amsterdam, The Netherlands)
16.45
Michael Reth (Freiburg, Germany)
17.30
Drinks and Dinner
Thorsten Mempel (Charlestown, USA )
Closure
14.15
Evening lecture
Chair: Esther de Jong
20.00 Clotilde Thery (Paris, France)
21.00
Party
March 2015
IMMUUN
33
NEWS
EU project COMPARE:
Supporting the global
fight against infectious diseases
The new 20 million euro EU project COMPARE in the Horizon 2020 program aims to reduce the impact and cost of infectious
disease outbreaks. To attain this goal, COMPARE strives to speed up worldwide detection of and response to infectious
disease outbreaks, both in human and in veterinarian settings. New genome technology should enable this. A consortium
on 28 institutes led by Erasmus MC Rotterdam and the National Food Institute of the Technical University of Denmark
Kopenhagen sees to the project’s execution. Other Dutch consortium partners are iBMG (The Institute of Health Policy and
Management) of Erasmus University Rotterdam, the AMC in Amsterdam, RIVM and Artemis Wildlife Health BV.
Human and animal health are under constant and increasing threat
of disease outbreaks around the globe caused by microorganisms
such as bacteria and viruses. Diseases are transmitted by foods or
the intervention of other vectors, such as mosquitos and midges.
New outbreaks occur and epidemics recur. Apart from the grieve
caused by mortality and disease, societal and economic impact
of these incidents and disasters can be huge. The pressure on
healthcare can be immense, production of livestock suffers,
confidence in food security and supply is hampered and trade and
economy can come to a standstill.
Swift action can see to it that outbreaks are contained and their
consequences remain relatively limited. The West-African Ebola-crisis
unfortunately proves that such swift action is not common practice
yet. The recent avian influenza outbreak equally demonstrates that a
pathogen can have a major international impact.
Real time global exchange
Predominant to limiting the consequences of outbreaks is being
able to quickly identify the microorganisms behind it. Within the
COMPARE framework, a global platform will be developed by using
new techniques for whole genome sequencing of pathogenic
microorganisms. This should result in a globally accessible databank.
The data should be exchanged in real-time to relate them to existing
insight about the mechanisms behind disease. The databank should
therefore also store knowledge on the properties of pathogens,
including the mechanisms these use and the transmissibility of the
viruses and bacteria between humans and animals. In addition,
information on treatment methods and infection prevention will
be included. Complex analyzes needed to examine the data will be
provided in an automated manner, so that even laboratories without
this expertise will henceforth be able to use it.
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IMMUUN
March 2015
The development of such a system must be carried out carefully, to
prevent wrong conclusions and wrongful warning calls. This is why
physicians, diagnostic laboratories, patient groups, governments,
the food industry and other businesses will be closely involved in
the development of the system.
One Health approach
Frank Møller Aarestrup from the Technical University of Denmark,
joint leader of the European consortium with Prof. Marion
Koopmans, head of Virology at Erasmus MC: “The aim is that the
platform can be used to harmonise the way scientists, authorities,
doctors and organisations around the world collect samples,
generate genome sequencing data and carry out risk assessments.
This new approach to disease surveillance will be able to
revolutionise the way we combat diseases globally.”
Zoonoses – diseases that can spread from animals and food
to humans – are the cause of many epidemics internationally.
For this reason COMPARE is based on a collaboration across
sectors and land borders and builds on the One Health approach.
The consortium unites doctors, veterinarians, virologists, and
microbiologists to develop the platform in collaboration with
epidemiologists and bioinformaticians. Koopmans: “The databank
information can be compared to all sorts of other available
information, such as clinical and epidemiological data, in a way
that is accessible to physicians, veterinarians and other end users.
This will enable us to detect new infectious disease outbreaks more
rapidly and in a better manner and to make better decisions on
appropriate measures to be taken to prevent further spread and on
the best treatment options for affected patients.”
Contact: m.koopmans@erasmusmc.nl
IMMuno VAllEy
ConsortIuM
Immuno Valley: connecting human and animal health
Immuno Valley is a business driven public-private consortium at the interface of human and
animal health. Immuno Valley’s highly qualified scientific and business partners collaborate in
order to translate R&D expertise into new products for the diagnosis, prevention and treatment
of infectious diseases.
Academia, businesses and SMEs active in the field of human and animal health are welcome to
join the Immuno Valley consortium of almost 40 scientific and business partners.
Immuno Valley partners benefit from:
overview of experts and their expertise
• Collaboration opportunities: academic and
including research facilities, in the field of
business partners find each other during
matchmaking events or are approached 1
to 1. In case a new call opens or other
infection and immunity in human and
animals.
• Event discounts: free or discounted tickets
funding opportunities arise, partners
for Immuno Valley Annual Conference,
interested in a certain topic are gathered for
theme-related symposia and matchmaking
joint proposal writing or advised on how to
proceed.
• Matchmaking: account contacts (twice per
year) on business opportunities and
events.
• Open communication channel: facilities to
publish your scientific or business case on
Immuno Valley’s website.
actualities resulting in customized advise
and professional support in finding suitable
partners and accessing new funds.
• Subsidy-alerts: Immuno Valley provides
up-to-date and personalized mailings about
new funding opportunities.
• Immuno Valley Expertise Database: Access
to the online expertise database offering an
More information
W www.immunovalley.nl
E info@immunovalley.nl
P +31 30 2531142
Mijke Vogels (accountmanager)
The Art of Saving a Life
Edward Jenner’s Smallpox Discovery
© Artwork by Alexia Sinclair
Set in an 18th century English doctor’s surgery, this stunning portrait features Dr. Edward Jenner inoculating James Phipps,
the first person to receive the smallpox vaccine. Dr. Jenner’s pioneering work in the late 18th century led to the eradication of
smallpox in 1980. Alexia created and photographed the entire tableau. The aristocratic woman in the center represents how
smallpox did not discriminate, affecting the rich and poor alike. The many flowers throughout the piece symbolize the global
impact of smallpox, and the skulls on every bottle the ephemeral nature of life and death.
This portrait by Alexia Sinclair 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!
www.gatesfoundation.org