Intra-operative Multi-Spectral Imaging Systems for radical

Intra-operative Multi-Spectral Imaging Systems for
radical tumor resection
Executive Summary
Cancer diagnosis has improved tremendously due to the development of non-invasive imaging
technologies like PET, SPECT, CT and MRI. Subsequently tumor tissue can be removed using open
surgery or minimal-invasive techniques like laparoscopy. It is of great importance that during surgery
tumor tissue is removed completely (radically) with sufficient tumor-free margin. However, the clinical
discrimination between tumor and normal tissue is difficult during the procedure. Especially during
laparoscopic surgery, the surgeon misses tactile information obtained via palpation and has to rely
fully on visual information.This makes non-radical resections (whereby the resection margins still
contain tumor cells) a serious clinical problem. In addition, metastatic spread in the lymphatic system
is difficult to identify during the surgical procedure.
In the MUSIS project we worked on the different aspects of this problem: technical, chemical and
translational;
•
Prof.Dr. Clemens Lowik
“The MUSIS project represents a unique collaboration
in the Netherlands between leading scientists, technical
universities, companies and surgeons, that will
revolutionize surgical oncology by providing surgeons
with a real-time near-infrared fluorescence-based tumor
imaging technique to guide surgery for radical resection
of tumor tissue and identification of sentinel nodes. By
allowing highly tailored surgical treatment, it could
significantly improve cancer survival rates.”
A special multispectral camera system with a customized
light source for both open and laparoscopic surgery has
been developed. The camera has been enhanced with
spectral unmixing software to improve the fluorescent signal
and for wide-field endogenous tissue characterization.
•
To provide the surgeon additional information during a
laparoscopic procedure, optical fibers which are used for
spectral analysis of specific tissue regions and a
miniaturized biopsy device which can get a tissue sample
from that tissue region, have been developed.
•
To visualize the tumor cells, two new near infrared
fluorescent tumor recognizing probes (EPCAM-CW800 and
cRGD-ZW800) have been developed. They have been
tested pre-clinically and are going through a toxicity
screening. Both probes are produced under GMP conditions
and will be clinically tested.
NIR-guided surgery promises:
For the surgeon:
improved outcomes and shorter
operations.
For the patient:
a more personalized care.
For the healthcare system:
lower costs through lower rates of
postoperative complications and
higher number of radical tumor
resections, eliminating the need
for re-operation.
The availability of these new tumor targeted NIRF-probes and the multispectral NIRF-camera systems
for Image Guided Surgery (IGS) makes it possible to visualize tumor tissue in real-time with high
precision and sensitivity and is expected to improve the rate of radical resections and probably also
patient survival. The camera systems are also used successfully for the recognition of sentinel lymph
nodes using non-targeted NIRF probes. With the translation of targeted probes to the clinic, image
based intra-operative identification of free tumor margins and local (lymph node) metastases becomes
possible and the percentage of radical tumor resections is expected to rise, accompanied by a greatly
improved life expectancy of cancer patients.
Translational Concept
The most important goal in oncologic surgery is complete removal of tumor lesions. This is particularly
challenging when the patient has been treated with neoadjuvant therapies, which induce scar tissue
and consequently complicate detection of tumor resection margins or remaining lesions.
Using tumor specific near-infrared fluorescence (NIRF) imaging, tumors can be clearly demarcated
during surgery. Better visualisation can reduce tumor-positive resection margins improving patient
outcome significantly.
In the MUSIS project we have been working in a multi-disciplinary team to translate technical, chemical
and biological ideas into a clinical usable solution. To visualize cancer cells during surgery, a nearinfrared camera with appropriate software is indispensable to detect targeted fluorescent probes. Small
biopsy devices in combination with optical fibers can provide additional information during laparoscopic
surgery. Close interaction of biologists, chemists and surgeons is required to provide feedback and to
do the evaluation.
All sub-solutions were first successfully tested in a pre-clinical setting using tumor cell lines and animal
models. The NIRF probes are in the process of being clinically evaluated.
CLINICAL NEED
TOOLS
A method that better visualizes tumor
tissue for the surgeon during surgical
resection of tumors. Complete removal
of tumor tissue results in improved
patient prospects.
Tumor specific near-infrared fluorescence probes and a camera system for image-guided
surgery. Improved instruments for precise resection and biopsies with minimal risk of cancer
spread.
Public-Private Partnership
4
GENERATE KNOWLEDGE…
…TRANSLATE INTO APPLICATIONS
…NEW CURE/CARE SOLUTIONS
APPLICATION
SCIENCE
PATIENT
Using intra-operative real-time near-infrared
fluorescent imaging we will tailor surgical
treatment in cancer patients for safe and
complete removal of tumors and affected
lymph nodes.
Academic partners
Supporting Foundations
Industrial partners
Organization and Partners
ADVICE
5
Advisory board
ISAC CTMM
DECISIONS
SteeringCie
Partner Representatives
CTMM
O2view/Quest
Innovations
Project Team
PI: Prof. C. Lowik (LUMC/EMC)
co-PI: Dr. Ir. J. Dijkstra (LUMC)
WP leaders (various)
Industrial partners (various)
Dr. E. Caldenhoven (CTMM)
NKI
DEAM
Westburg
LUMC
TU Delft
OPERATIONS
CTMM
Partners
Coordination
Finance
Publications
Workpackage leaders
WP1: Dr. E. Kaijzel (LUMC)
WP2: Prof. B. Lelieveldt (LUMC)
WP3: Prof. P. Breedveld (TUD)
WP4: Dr. A. Vahrmeijer (LUMC)
ARA
EMC
Luminostix
CTMM
Percuros
Budget: CTMM manages the flow of funds
6
Funding:
- 25% Academia
- 25% Industrial
- 50% Government Subsidy
Project costs:
- Personnel
- Materials
- Use of existing equipment
- Investments
- Third parties
- Management (5%)
Facts & Figures
7
Academic partners
Budget
Start
End
Partners
Industrial Partners Large
Distribution of the
MUSIS consortium
budgets to perform the
R&D activities
8.7 M €
2009
2015
10
Industrial Partners SME
Investments
CASH COSTS
1.500.000
1.000.000
Academic cash costs
Industrial cash costs
500.000
0
PhD
PostDoc
Sen. Staff
Supp. Staff
IT Staff
M&S
Investments
KIND COSTS
1.500.000
1.000.000
Academic in kind costs
Industrial in kind costs
500.000
0
PhD
PostDoc
Sen. Staff
Supp. Staff
IT Staff
M&S
Investments
Facts & Figures
Budget
Start
End
Partners
Persons
FTE
8.7 M €
2009
2015
10
43
58 (5 years period)
Output
No
Papers
32
13 papers in submission - mean impact factor all published MUSIS papers: 3,1
Theses
6
2 planned for 2016
Personal
Grants
0
Patent fillings
0
Spin-off
Companies
0
Raising
Capital
4
Awards
0
Public
Media
0
KWF (EpCAM €571960) / Bas Mulder (W&W rectum €728000) / KWF Probe (€189000) / ERC Survive (€2487600)
Scientific Value Creation - Breakthroughs
•
•
•
•
•
•
•
•
•
•
Preclinical testing and validation of both commercially available NIRF probes and new tumor targeting
agents in mouse models of different forms of cancer showed their potential use for clinical translation. This
led to the planned clinical evaluations of RGD and EpCam.
Improved signal processing of the camera both for the open and laparoscopic system by using spectral
unmixing techniques to get a better tumor to background ratio
Developing techniques for real-time algorithms to correct for photon-tissue interaction for better
localization and detection of deeper signal sources.
Creating new steerable devices using 3D printing techniques to guide glass fibers for optical biopsies.
Differential Pathlength Spectroscopy (DPS) systems have been developed using glass fibers that are
positioned on suspicious tissue spots to perform an optical measurement that quantifies a number of
parameters of the microvasculature such as the oxygen saturation of the tissue via the absorption.
Development of an opto-mechanical biopsy devices which enables extremely precise harvesting of tissue
samples at the exact location of the DPS measurement. Besides evaluating DPS, the devices can also be
used as stand alone instruments for high precision biopsy.
NIR fluorescence imaging of colorectal liver metastases, even when used with a non-targeted NIR
fluorophore, is complementary to conventional imaging and able to identify missed lesions by other
modalities
Real-time intraoperative NIR fluorescence imaging with a tumor-specific agent is feasible, safe and
clinically useful. More malignant lesions were identified using two tumor specific agents targeting the folate
receptor-alpha in patient with ovarian cancer. These lesions were not identified by conventional inspection
and palpation
The first batch of GMP (clinical) grade tumor specific cRGD-ZW800-1 probe for NIR intra-operative
detection of tumors has been manufactured. The material has been proven safe in preclinical safety (tox)
studies. The first clinical study in healthy volunteers is to start in May 2016
Preclinical development of a tumor specific agent EpCAM-CW800-1 is being finalized potentially suitable
for intra-operative visualization of a wide variety of tumors. First clinical evaluation is planned for 2016.
Highest Impact Papers – mean 5,0
1.
Mioeg J.S. et al, Breast Cancer Res Treat. 2011 Aug;128(3):679-89
2.
Goossens-Beumer I.J. et al., Br J Cancer. 2014 Jun 10;110(12):2935-44
3.
Keereweer S. et al, Int J Cancer. 2012 Oct 1;131(7):1633-40
4.
Van Driel P.B. et al, Int J Cancer. 2014 Jun 1;134(11):2663-73
5.
Hutteman, M. et al, Am J Obstet Gynecol. 2012 Jan;206(1):89.e1-5
Mean Impact Factor
1
International - oncology
2
4,4
CTMM - oncology
6,8
0
2
4
1 - Panaxea 2013. Steute et al Impact Analysis CTMM (internal report, paper in preparation).
2 - Mean impact factor based on 200 papers from the CTMM oncology first call projects.
6
8
10
Scientific Value Creation - Theses
Thesis
Partner
Year
Sven Mieog
LUMC
2011
Merlijn Hutteman
LUMC
2011
BangWen Xie
LUMC
2013
Joost van der Vorst
LUMC
2014
Floris Verbeek
LUMC
2015
Filip Jelinek
TU Delft
2015
Quirijn Tummers
LUMC
2016
Mark Boonstra
LUMC
2016
Scientific Value Creation - Infrastructure
• The Artemis handheld camera system for both
open and minimal invasive surgery which show
simultaneously the color image and the fluorescent
overlay. Furthermore equipped with a tunable light
source to have optimal settings for the different
fluorescent dyes simultaneously
Optimal real-time spectral unmixing
• A constrained spectral unmixing method, which
limits estimated fluorescent intensities to physically
feasible quantities was developed and implemented
for real-time unmixing (> 300 frames per second).
Real-time 3D optical tissue characterization
• Word’s first 3D-printed steerable surgical
instruments equipped with a minimum number of
structural components
• Method to acquire the same information through
simultaneous projections of patterns in different
directions and image processing
• Novel, highly accurate, bio-inspired optomechanical biopsy device successfully evaluated
in-vivo
A unique one-stop-shop infrastructure is created
combining expertise and logistics for a fast, high
quality translation from preclinical validation to human
studies of (tumor specific) near fluorescent imaging
applications.
• Camera system development suitable for preclinical
and clinical work
• Preclinical probe development (synthesis,
pharmaceutical development, in vitro and in vivo
evaluation, all IND enabling studies)
• GMP manufacturing facility according to EMA
and FDA standards
• Clinical evaluation in healthy volunteers
• Clinical evaluation in patients
• This is a first time proof that full-field real-time
optical property imaging is feasible
Equipment
Data-driven
Methods
Infrastructure for
clinical
translation
Molecular
Diagnostics
& Imaging
Tumor specific near infrared fluorescent probes
• cRGD-ZW800-1, an 800 nm fluorophore (ZW8001) conjugated to a peptide (cRGD), which targets
integrins associated with the formation of new
blood vessels in tumors
• EpCAM-Fab/800CW, a humanized Fab antibody
fragment against an overexpressed target on tumor
cells conjugated to 800CW, which is optimized for
clinical purposes by de-immunization
12
Clinical and Economic Value Creation of
MUSIS
New ‘products’ for clinical care
Quest Spectrum system for open and laparoscopic surgery
PRODUCT
PATIENT
Progess obtained in translational pipeline
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
•
The ability to do both open and
minimal invasive surgery.
•
To show the color image and
the fluorescent overlay at the
same time.
For the dispersion of fluorescent imaging during
surgery two kinds of partnership are essential for
the camera system:
•
To be able to visualize two
fluorophores at the same time
•
To have the highest sensitivity
and contrast.
•
To show the images in HD
Probe developers: The optimal combination is
camera with probes that highlight tumors and vital
structures such as nerves. These targeted probes
will start getting on the market in 2018. The
camera is optimized for the individual probes to
strive for the best clinical outputs.
The system combines all these features and
is being successfully used in numerous
hospital world wide.
The system is constantly being upgraded to
assure ease of use.
Also new functionality is being tested and will
be added in the near future such as
oxygenation measurement
rapy selection
The
Discovery
Pathways
biomarkers
Progress within CTMM
2008
2014
Research hospitals: When using the system
surgeons find new applications in which
fluorescent imaging helps improve the result of
surgery. Also for effective translation of
this technique to the operation room,
large numbers of patients need to
be included in trials to validate
the outcomes.
Economic viability: Fast growing number of
applications with non targeted probes, the positive
development with targeted probes and the growing
interest shown in the market result in a positive outlook.
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
Tumor targeting
Vital organ sparing
tic innovat
gnos
ion
Dia
The Quest Spectrum Platform
aims to be the most
optimal system on the
market. Key elements
to achieve this are:
PARTNERSHIP
Imaging perfusion
and sentinal lymph nodes
System and probe development help to
improve patient outcomes by:
•
Showing the edges of tumors making
radical resection easier without removing
more tissue then necessary.
•
Avoiding damaging vital, often hard to
identify tissue by making them fluorescent
•
Making laparoscopic surgery possible
because the lack of palpation is replaced
by color coding.
Optimal real-time spectral unmixing
We proposed a method to determine the
optimal filter settings for multi-spectral
imaging, based on measured spectra of
fluorescent agents.
Bulk
Evaluation on
Pre-clinical
acquisitions
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2014
An optimal method for filter selection was
developed and evaluated on pre-clinical data.
A constrained spectral unmixing method, which
limits estimated fluorescent intensities to
physically feasible quantities was developed and
implemented for real-time unmixing (> 300 frames
per second).
Pre-clinical evaluation of the optimal unmixing
method showed a comparable accuracy in
estimated fluorophore intensities with 4 bands,
compared to a 23 band acquisition with minimal
increase in noise levels.
4 channels
rapy selection
The
Method
development
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
Number of patients per year: > 1.2 million
Total healthcare cost per year: $US 14-22 billion
Scientific
Multiple probes with
overlapping spectra can be imaged in realtime
Societal
Multiple fluorescent markers
allow simultaneous tumor and vulnerable
tissue for more effective and safer surgery
Vasculature
23 channels
Lesion
Progess obtained in translational pipeline
tic innovat
gnos
ion
Dia
Recently, fluorescence guided surgery has
been introduced to help the surgeon to
identify tumors intra-operatively. Imaging
multiple markers is useful for the visualization
of multiple tumor regions (edge, bulk) and
vulnerable tissue (e.g. bile ducts). Current
intraoperative cameras in general image with
a single near-infrared channel and do not
allow the separation of different markers or
the suppression of tissue auto-fluorescence.
Multispectral imaging does allow this
separation, through spectral unmixing, but
real-time intra-operative imaging imposes
constraints on the imaging hardware that limit
the number of spectral bands that can be
imaged.
Future outlook
The optimal filter selection and constrained spectral unmixing
are ready to be implemented in clinically approved cameras
to enable simultaneous multi-probe imaging.
Economic
A decrease in repeated
surgery and avoidance of damaging bodily
functions decreases medical and patient
recovery related costs.
Together with Quest MI, the proposed
multispectral imaging will be brought to the
clinic.
Real-time 3D optical tissue characterization
Raw data
Profile
Reflectance
AC
DC
Phase
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2014
With the proposed projection and processing
methods, 3D-SSOP enables real-time wide-field
acquisition of optical properties and surface
profile.
rapy selection
The
Validation in
large animals
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
Estimating AC and DC reflectance and phase
using spatial filtering is unbiased, compared to
SFDI. However, the use of spatial information
limits resolution.
3D-SSOP
3D-SFDI
Difference
ࣆࢇ (mm−1)
In collaboration with Sylvain Gioux (Harvard
Medical School), we proposed and validated
a method to acquire the same information
through simultaneous projections of patterns
in different directions and image processing.
Development
of real-time
optical tissue
property
imaging
Height (cm) ࣆ࢙ᇱ (mm-1)
Using Spatial Frequency Domain Imaging
(SFDI), full-field measurements of optical
properties are possible, but the currently
used modulated imaging approach requires 9
images for full tissue characterization on
irregular surfaces, such as found in patients.
Progess obtained in translational pipeline
tic innovat
gnos
ion
Dia
During surgery, measuring the endogenous
optical properties of the patient tissue has a
wide variety of applications. Particular
examples are quantitative blood volume and
oxygenation measurements and the
calibration of fluorescence intensity. Most
techniques for these measurements make
point measurements through fibers, which
prevents imaging of the full surgical field.
Future outlook
The proposed method is implemented on a clinically
approved camera system (FLARE, Boston) and validation will
move shortly from large animals to in-human imaging.
Number of patients per year: > 1.2 million
Total healthcare cost per year: $US 14-22 billion
Scientific
We have shown for the first
time that full-field real-time optical property
imaging is feasible.
Societal
Real-time blood perfusion
imaging has a wide variety of surgical
applications, from flap reconstructions to
incision determination.
Economic
Better perfusion imaging,
e.g. in flap reconstructions allow faster
assessment of tissue viability, which
operating time and prevents repeated
surgery.
Development of multi-spectral systems for endoscopic
applications – Steerable instruments
Progess obtained in translational pipeline
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2014
A thorough patent survey has been conducted on
existing steerable instruments. Based on the
outcomes of this survey, a series of novel
steerable instruments has been manufactured
using additive 3D printing technology. Our
steerable instruments, called “DragonFlex” are
unique in that they represent world’s first 3D
printed steerable tools equipped with a theoretic
minimum of only 7 structural components.
rapy selection
The
Discovery
Pathways
biomarkers
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Suspicious spots in a multi-spectral image
may represent cancer but can also turn out to
be harmless artefacts. To validate whether
suspicious spots really represent tumorous
tissue, within MUSIS WP3, Differential
Pathlength Spectroscopy (DPS) systems
have been developed using glass fibers that
are positioned on suspicious tissue spots to
perform an optical measurement that
quantifies a number of parameters of the
microvasculature. For a correct DPSmeasurement, the glass fibers have to be
positioned nearly perpendicular to the tissue.
To enable precise aiming of glass fibers in a
minimally invasive setting, novel steerable
instruments have been developed. Besides
the combination with DPS, our instruments
can also be equipped with standard tools
such as surgical grippers.
Number of patients per year: > 1.2 million
Total healthcare cost per year: $US 14-22 billion
Scientific
Word’s first 3D-printed
steerable surgical instruments equipped with
a minimum number of structural components.
Societal
3D printing of dedicated
instruments may revolutionize the future of
surgery with adaptability of instrument
designs to individual procedures and
patients.
Future outlook
3D printing of dedicated instruments may revolutionize the
future of surgery with a large cost reduction and adaptability
of instrument designs to individual procedures and patients.
Economic
Less dependency on medical
companies and large freedom in instrument
designs is expected to lead to a large cost
reduction of medical instrumentation.
Development of multi-spectral systems for endoscopic
applications – Opto-mechanical biopsy
Progess obtained in translational pipeline
Selection
Pathways
biomarkers
Demonstrator
Development
device
Clinical
Evaluation
cohorts
Market acces
Progress within CTMM
2008
2014
A thorough patent survey has been conducted on
existing opto-mechanical biopsy instruments.
Based on the outcomes of this survey, a new
Ø6mm prototype biopsy harvester has been
developed combining DPS with high precision
mechanical biopsy using a novel bio-inspired
crown cutter based on the “Aristotle’s Lantern”
chewing apparatus in sea urchins. The biopsy
harvester has been successfully evaluated in a
series of in-vivo experiments on mice at the
Erasmus MC. Currently, an improved Ø5mm
device is being manufactured suitable for use in
combination with the “DragonFlex” steerable
instrument developed within CTMM MUSIS WP3.
rapy selection
The
Discovery
Pathways
biomarkers
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Suspicious spots in a multi-spectral image
may represent cancer but can also turn out to
be harmless artefacts. To validate whether
suspicious spots really represent tumorous
tissue, within MUSIS WP3, Differential
Pathlength Spectroscopy (DPS) systems
have been developed using glass fibers that
are positioned on suspicious tissue spots to
perform an optical measurement that
quantifies a number of parameters of the
microvasculature such as the oxygen
saturation of the tissue via the absorption and
scattering of the scattered light in the tissue.
In order to evaluate DPS, opto-mechanical
biopsy devices have been developed
enabling extremely precise harvesting of
tissue samples at the exact location of the
DPS measurement. Besides evaluating DPS,
the devices can also be used as stand alone
instruments for high precision biopsy.
Number of patients per year: > 1.2 million
Total healthcare cost per year: $US 14-22 billion
Scientific
Novel, highly accurate, bioinspired opto-mechanical biopsy device
successfully evaluated in-vivo.
Societal
Accurate, fast and safe
method of measuring tissue properties
without the risk of cancer spread as with
conventional biopsy.
Future outlook
Optical biopsy using DPS as an alternative, accurate and
safe method of measuring tissue properties without a risk of
cancer spread.
Economic
Smaller risk of cancer
spread, less need for laborious laboratory
tests on tissue samples.
Targeted probe for image guided surgery of colorectal cancer
Discovery
Pathways
biomarkers
Selection
Pathways
biomarkers
Demonstrator Clinical
Development Evaluation
device
cohorts
Progress within CTMM
Market acces
2016
After realizing conditions and requirements for
preclinical evaluation of near-infrared fluorescence
imaging, cRGD-ZW800-1 was successfully validated in
different mouse models, including colorectal and
pancreatic cancer. Subsequently, the probe was
produced under GMP conditions for clinical use.
To visualize NIR probes intraoperatively,
a
novel,
NIR
fluorescence imaging system was
developed (Artemis, Quest medical
imaging)
Previously,
NIR
fluorescence
imaging using nonspecific, clinically
available
fluorophores
was
successfully performed in patients
with different types of cancer using
the Artemis camera system.
cRGD-ZW800-1 is now ready to be tested in humans.
Safety and pharmacology studies will be performed in
healthy volunteers. After these steps, cRGD-ZW800-1
is ready to be tested in patients, with the aim of
improving surgical outcome.
Fig 1. Intraoperative imaging of orthotopic colon tumors. Shown
are two examples of cRGD-ZW800-1 administered intravenously,
which allowed clear tumor identification using NIR fluorescence in
orthotopic colon tumor bearing mice. H&E and fluorescence
overlay of the border between tumor and normal colon tissue.
Verbeek et al. Ann Surg Oncol, 2014
Future outlook
Image-guided surgery using NIR-based fluorescent
probes will find its way to the clinic and will assist in
cancer surgery to improve prospects for cancer
patients
rapy selection
The
Here we developed cRGD-ZW800-1, an 800 nm
fluorophore (ZW800-1) conjugated to a peptide
(cRGD), which targets integrins associated with
the formation of new blood vessels in tumors. The
RGD sequence forms a powerful tool for tumor
targeting: with high affinity for either the cancer
cells, the supporting vascular cells, or both cell
types, the large majority of tumors may be
targeted with the same peptide.
Progess obtained in translational pipeline
Treatment Screening
& monitoring prevention
Patient Early
stratification diagnosis
tic innovat
gnos
ion
Dia
In many cases of cancer, surgery is the only
curative treatment. Currently, the surgeon mainly
relies on visual and palpable feedback during
surgery. Intraoperative near-infrared (NIR, 700 –
900 nm) fluorescence imaging is an innovative
method which can be used to identify tumors. By
using fluorophores conjugated to tumor targeting
peptides, NIR fluorescence imaging can identify
and demarcate tumors. By doing so, it provides a
very useful tool to reduce positive resection
margins which may improve patient outcome.
Number of patients per year: > 1.2 million
Total healthcare cost per year: $US 14-22 billion
Scientific
Image-guided surgery (IGS) with untargeted
probes has already shown to be a useful and
feasible technique for oncologic surgery.
Societal
The prospects of (colo)rectal cancer patients
will be improving when surgical treatment will
be more efficient using IGS with tumortargeting agents.
Economic
Tumor targeted IGS results in less reoperations and extra treatment.
Targeted probe for image guided surgery of colorectal cancer
Discovery
Pathways
biomarkers
Selection
Pathways
biomarkers
Clinical
Evaluation
cohorts
Market acces
2016
rapy selection
The
Progress within CTMM
Demonstrator
Development
device
One of the most promising targets is EpCAM
(epithelial cell adhesion molecule). This cell membrane
molecule, is homogeneously over-expressed in more
than 85% of all colorectal tumors (Figure 1 and 2).
MUSIS has evaluated several EpCAM targeting
compounds, including peptides, aptamers, full-size
antibodies and antibody fragments in conjugation with
the NIRF dye 800CW for the purpose of fluorescence
guided surgery.
The best performing compound was a humanized Fab
antibody fragment conjugated to 800CW, which was
consequently optimized for clinical purposes by deimmunization and removal of a his-tag: EpCAMFab/800CW.
Fig 3: Athymic subcutaneous mice model with HT29 cells (human colon
carcinoma; moderate EpCAM expression). After tail injection of 0.25 nmol
EpCAM-FAB/800CW, tumors could clearly be identified 24 hours after
administration (upper row), whereas a control probe (Fab-CNT) did not
result in tumor identification. Histology images in the right column show
fluorescence targeting of tumors by EpCAM-FAB/800CW after 48 hours.
Fig 4: Tumor-to-background
ratio (TBR) over time.
A sufficient TBR (>2.5) is
achieved from 24 hours after
administration of EpCAM FAB/800CW up to 96h.
The production proces is scaled-up to clinical scale and GMP
production is underway. The first clinical studies will be done
in healthy volunteers followed by rectal cancer patients to
evaluate the improvement in complete tumor resection.
Fig 1: EpCAM expression in various
cancer, Spizzo et al, J Clin Path, 2011
Fig 2: EpCAm staining in colorectal
cancer, Goossens-Be et al,
Br Journal Cancer, 2014
Future outlook
Image-guided surgery using NIR-based fluorescent
probes will find its way to the clinic and will assist in
cancer surgery to improve prospects for cancer patients
Treatment
& monitoring
Screening
prevention
Patient
stratification
Early
diagnosis
tic innovat
gnos
ion
Dia
Surgery is the primary care for achieving curation in
many cancer types. Complete resection of tumor
tissue is of utmost importance for prognosis. However,
recognition of tumor tissue can be challenging during
surgery. In (colo)rectal cancer, intra-operative tumor
margin detection remains difficult and as a
consequence tumor involvement at resection margins
occurs. Real-time visualization of the tumor by
targeted near-infrared fluorescence (NIRF) imaging
may solve this problem.
Number of patients per year: > 1.2 million
Total healthcare cost per year: $US 14-22 billion
Scientific
Image-guided surgery (IGS) with untargeted
probes has already shown to be a useful and
feasible technique for oncologic surgery.
Societal
The prospects of (colo)rectal cancer patients
will be improving when surgical treatment will
be more efficient using IGS with tumortargeting agents.
Economic
Tumor targeted IGS results in less reoperations and extra treatment.
Partners
Delft University of Technology (TU Delft)
Delft
Erasmus University Medical Center (EUMC)
Rotterdam
Leiden University Medical Center (LUMC)
Leiden
Netherlands Cancer Institute (NKI)
Amsterdam
Antibodies for Research Applications BV (ARA)
Gouda
DEAM B.V.
Amsterdam
Luminostix B.V.
Rotterdam
O2View B.V.
Middenmeer
Percuros B.V.
Enschede
Quest Medical Imaging B.V.
Middenmeer
Westburg B.V.
Leusden
List of Publications
1. Handgraaf HJ, Boogerd LS, Verbeek FP, Tummers QR, Hardwick JC, Baeten CI, Frangioni JV, van de Velde CJ, Vahrmeijer AL. Intraoperative fluorescence imaging to localize tumors and
sentinel lymph nodes in rectal cancer. Minim Invasive Ther Allied Technol. 2016 Feb;25(1):48-53
2. Jelinek F, Arkenbout E, Henselmans P, Pessers R, Breedveld P. Classification of Joints Used in Steerable Instruments for MIS – A State of the Art Review. Journal of Mechanical Design,
March 2015, Vol. 9/ 010801-1
3. Stegehuis PL, MC, Karien De Rooij E, Powolny FE, Sinisi R, Homulle H, Bruschini CE, Charbon E, Van De Velde CJH, Lelieveldt BPPF, Vahrmeijer AL, Dijkstra J, Van De Giessen M,
Fluorescence lifetime imaging to differentiate bound from unbound ICG-cRGD both in vitro and in vivo. SPIE BiOS, 93130O-93130O-6, 2015
4. Tummers QR, Verbeek FP, Prevoo HA, Braat AE, Baeten CI, Frangioni JV, van de Velde CJ, Vahrmeijer AL. First experience on laparoscopic near-infrared fluorescence imaging of hepatic
uveal melanoma metastases using indocyanine green. Surg Innov. 2015 Feb;22(1):20-5
5. van de Giessen M, Angelo JP, Gioux S. Real-time, profile-corrected single snapshot imaging of optical properties. Biomed Opt Express. 2015 Sep 21;6(10):4051-62
6. Van de Giessen M, Schaafsma BE, Charehbili A, Smit VTHBM, Kroep JR, Boudewijn, L elieveldt BPF, Liefers GJ, Chan A, Löwik CWGM , Dijkstra J, van de Velde CJH, Wasser MNJM,
Vahrmeijer AL, Early identification of non-responding locally advanced breast tumors receiving neoadjuvant chemotherapy, SPIE BiOS, 93032K-93032K-7, 2015
7. Verbeek FP, Tummers QR, Rietbergen DD, Peters AA, Schaafsma BE, van de Velde CJ, Frangioni JV, van Leeuwen FW, Gaarenstroom KN, Vahrmeijer AL. Sentinel Lymph Node Biopsy
in Vulvar Cancer Using Combined Radioactive and Fluorescence Guidance. . Int J Gynecol Cancer. 2015 Jul;25(6):1086-93
8. Boonstra MC, Verbeek FP, Mazar AP, Prevoo HA, Kuppen PJ, van de Velde CJ, Vahrmeijer AL, Sier CF. Expression of uPAR in tumor-associated stromal cells is associated with
colorectal cancer patient prognosis: a TMA study. BMC Cancer. 2014 Apr 17;14:269
9. Boonstra MC, Verbeek FP, Mazar AP, Prevoo HA, Kuppen PJ, van de Velde CJ, Vahrmeijer AL, Sier CF. Expression of uPAR in tumor-associated stromal cells is associated with
colorectal cancer patient prognosis: a TMA study. BMC Cancer. 2014 Apr 17;14:269
10.Goossens-Beumer IJ, Zeestraten EC, Benard A, Christen T1, Reimers MS, Keijzer R, Sier CF, Liefers GJ, Morreau H, Putter H, Vahrmeijer AL, van de Velde CJ, Kuppen PJ. Clinical
prognostic value of combined analysis of Aldh1, Survivin, and EpCAM expression in colorectal cancer. Br J Cancer. 2014 Jun 10;110(12):2935-44
11.Jelínek F, Goderie J, van Rixel A, Stam D, Zenhorst J, Breedveld P. Bioinspired Crown-Cutter—The Impact of Tooth Quantity and Bevel Type on Tissue Deformation, Penetration Forces,
and Tooth Collapsibility. J. Med. Devices 8(4), 041009, Aug 19, 2014)
12.Jelínek F, Pessers R, Breedveld P, DragonFlex Smart Steerable Laparoscopic Instrument. J. Med. Devices 8(1), 015001 (Jan 07, 2014)
13.Jelínek F, Smit G, Breedveld P, Bioinspired Spring-Loaded Biopsy Harvester—Experimental Prototype Design and Feasibility Tests. J. Med. Devices 8(1), 015002 (Jan 20, 2014
14.Schaafsma BE, Verbeek FP, Elzevier HW, Tummers QR, van der Vorst JR, Frangioni JV, van de Velde CJ, Pelger RC, Vahrmeijer AL. Optimization of sentinel lymph node mapping in
bladder cancer using near-infrared fluorescence imaging. J Surg Oncol. 2014 Dec;110(7):845-50
15.van Driel PB, van der Vorst JR, Verbeek FP, Oliveira S, Snoeks TJ, Keereweer S, Chan B, Boonstra MC, Frangioni JV, van Bergen en Henegouwen PM, Vahrmeijer AL, Lowik CW.
Intraoperative fluorescence delineation of head and neck cancer with a fluorescent anti-epidermal growth factor receptor nanobody. Int J Cancer. 2014 Jun 1;134(11):2663-73
16.Verbeek FP, Schaafsma BE, Tummers QR, van der Vorst JR, van der Made WJ, Baeten CI, Bonsing BA, Frangioni JV, van de Velde CJ, Vahrmeijer AL, Swijnenburg RJ. Optimization of
near-infrared fluorescence cholangiography for open and laparoscopic surgery. Surg Endosc. 2014 Apr;28(4):1076-82
17.Verbeek FP, Troyan SL, Mieog JS, Liefers GJ, Moffitt LA, Rosenberg M, Hirshfield-Bartek J, Gioux S, van de Velde CJ, Vahrmeijer AL, Frangioni JV. Near-infrared fluorescence sentinel
lymph node mapping in breast cancer: a multicenter experience. Breast Cancer Res Treat. 2014 Jan;143(2):333-42
18.Blok EJ, Kuppen PJ, van Leeuwen JE, Sier CF. Cytoplasmic Overexpression of HER2: a Key Factor in Colorectal Cancer. Clin Med Insights Oncol. 2013;7:41-51
19.Park D, Xie BW, Van Beek ER, Blankevoort V, Que I, Löwik CW, Hogg PJ. Optical imaging of treatment-related tumor cell death using a heat shock protein-90 alkylator. Mol Pharm. 2013
Oct 7;10(10):3882-91
20.van der Vorst JR, Schaafsma BE, Verbeek FP, Keereweer S, Jansen JC, van der Velden LA, Langeveld AP, Hutteman M, Löwik CW, van de Velde CJ, Frangioni JV, Vahrmeijer AL. Nearinfrared fluorescence sentinel lymph node mapping of the oral cavity in head and neck cancer patients. Oral Oncol. 2013 Jan;49(1):15-9.
21.Hutteman M, van der Vorst JR, Gaarenstroom KN, Peters AA, Mieog JS, Schaafsma BE, Löwik CW, Frangioni JV, van de Velde CJ, Vahrmeijer AL. Optimization of near-infrared
fluorescent sentinel lymph node mapping for vulvar cancer. Am J Obstet Gynecol. 2012 Jan;206(1):89.e1-5
22.Keereweer S, Kerrebijn JD, Mol IM, Mieog JS, Van Driel PB, Baatenburg de Jong RJ, Vahrmeijer AL, Löwik CW. Optical imaging of oral squamous cell carcinoma and cervical lymph node
metastasis. Head Neck. 2012 Jul;34(7):1002-8
23.Keereweer S, Mol IM, Vahrmeijer AL, Van Driel PB, Baatenburg de Jong RJ, Kerrebijn JD, Löwik CW. Dual wavelength tumor targeting for detection of hypopharyngeal cancer using nearinfrared optical imaging in an animal model. Int J Cancer. 2012 Oct 1;131(7):1633-40
24.Smith BA, Xie BW, van Beek ER, Que I, Blankevoort V, Xiao S, Cole EL, Hoehn M, Kaijzel EL, Löwik CW, Smith BD. Multicolor fluorescence imaging of traumatic brain injury in a
cryolesion mouse model. ACS Chem Neurosci. 2012 Jul 18;3(7):530-7
25.van de Giessen M, van der Laan A, Hendriks EA, Vidorreta M, Reiber JH, Jost CR, Tanke HJ, Lelieveldt BP. Fully automated attenuation measurement and motion correction in FLIP
image sequences. IEEE Trans Med Imaging. 2012 Feb;31(2):461-73
26.van der Vorst JR, Schaafsma BE, Verbeek FP, Hutteman M, Mieog JS, Lowik CW, Liefers GJ, Frangioni JV, van de Velde CJ, Vahrmeijer AL. Randomized comparison of near-infrared
fluorescence imaging using indocyanine green and 99(m) technetium with or without patent blue for the sentinel lymph node procedure in breast cancer patients. Ann Surg Oncol. 2012
Dec;19(13):4104-11
27.van der Vorst JR, Vahrmeijer AL, Hutteman M, Bosse T, Smit VT, van de Velde CJ, Frangioni JV, Bonsing BA. Near-infrared fluorescence imaging of a solitary fibrous tumor of the
pancreas using methylene blue. World J Gastrointest Surg. 2012 Jul 27;4(7):180-4
28.Verbeek FP, van der Vorst JR, Schaafsma BE, Hutteman M, Bonsing BA, van Leeuwen FW, Frangioni JV, van de Velde CJ, Swijnenburg RJ, Vahrmeijer AL. Image-guided
hepatopancreatobiliary surgery using near-infrared fluorescent light. J Hepatobiliary Pancreat Sci. 2012 Nov;19(6):626-37
29.Xie BW, Mol IM, Keereweer S, van Beek ER, Que I, Snoeks TJ, Chan A, Kaijzel EL, Löwik CW. Dual-wavelength imaging of tumor progression by activatable and targeting near-infrared
fluorescent probes in a bioluminescent breast cancer model. PLoS One. 2012;7(2):e31875
30.Mieog JS, Hutteman M, van der Vorst JR, Kuppen PJ, Que I, Dijkstra J, Kaijzel EL, Prins F, Löwik CW, Smit VT, van de Velde CJ, Vahrmeijer AL. Image-guided tumor resection using realtime near-infrared fluorescence in a syngeneic rat model of primary breast cancer. Breast Cancer Res Treat. 2011 Aug;128(3):679-89
31.van der Vorst JR, Hutteman M, Gaarenstroom KN, Peters AA, Mieog JS, Schaafsma BE, Kuppen PJ, Frangioni JV, van de Velde CJ, Vahrmeijer AL. Optimization of near-infrared
fluorescent sentinel lymph node mapping in cervical cancer patients. Int J Gynecol Cancer. 2011 Nov;21(8):1472-8
32.Keereweer S, Kerrebijn JD, van Driel PB, Xie B, Kaijzel EL, Snoeks TJ, Que I, Hutteman M, van der Vorst JR, Mieog JS, Vahrmeijer AL, van de Velde CJ, Baatenburg de Jong RJ, Löwik
CW. Optical image-guided surgery--where do we stand? Mol Imaging Biol. 2011 Apr;13(2):199-207
Abbreviations
23
CT
Computed Tomography
DPS
Differential Pathlength Spectroscopy
EMA
European Medicines Agency
EpCAM
Epithelial cell adhesion molecule
FDA
Food and Drug administration
GMP
Good Manufacturing Practices
IGS
Image Guided Surgery
MRI
Magnetic Resonance Imaging
NIRF
Near-infrared fluorescence
PET
Positron Emission Tomography
RGD
tripeptide Arg-Gly-Asp
SPECT
Single Photon Emission Computed Tomography
SFDI
Spatial Frequency Domain Imaging
24
Co funded by
International
Scientific Advisory
Committee
Prof. R.S. Reneman, Ph.D. (Chair)
Prof. J.A. Andersson, M.D., Ph.D.
J.P. Armand, M.D., MSc.
R.S.B. Balaban, Ph.D.
J.B. Bassingthwaighte, Ph.D.
R.G. Blasberg, M.D.
Prof. L. Degos
H. Hermjakob, Ph.D.
W.J. Jagust, Ph.D.
Prof. D.J. Kerr
Prof. U.D.A. Landegren, M.D., Ph.D.
R.I. Pettigrew, M.D., PhD.
A. Tedgui, Ph.D.
Prof. T.P. Young
Center for Translational
Molecular Medicine
High Tech Campus 84
5656 AG Eindhoven, The Netherlands
T +31 (0)40 800 23 00
F +31 (0)40 800 23 15
[email protected] | www.ctmm.nl
Chamber of Commerce 17198356
31 October 2015