Advanced imaging for better decision-taking in colorectal cancer: AdvantageCRC
Colorectal cancer (CRC) ranks as the fourth most commonly occurring cancer in Belgium, with a yearly incidence of over 7000 new patients. Surgical resection is the primary therapeutic option for local or locally advanced cancer patients, as surgery remains the most effective treatment for these solid tumors. However, surgeons primarily rely on their visual and tactile senses to distinguish cancerous tissue from healthy tissue. Unfortunately, as the surgeons’ senses are neither sufficiently specific nor sensitive, imperfect surgeries can lead to over- and under-treatment. On the one hand, total resection of all cancerous tissue is essential to exclude the recurrence of malignancy. On the other hand, removing too much surrounding tissue increases the risk of postoperative complications. This is especially the case in patients diagnosed with locally advanced CRC. These patients undergo neoadjuvant therapies with chemo- and/or radiotherapy before surgical removal of the remaining tumor lesion(s). While these initial therapies can significantly benefit patients' survival, they can also hinder the surgical removal of the tumor due to the formation of large amounts of fibrotic tissue.
Fortunately, advances in surgical sciences have resulted in the development of targeted fluorescence-guided surgery (FGS). FGS is an emerging technique in which fluorescent contrast agents are injected before surgery that accumulate in specific tissues and allow the intraoperative imaging of the targeted regions. By allowing the surgeon to distinguish malignant from its surrounding benign tissue, we expect to help the patient on three important levels: (1) improving the complete removal of the tumor while sparing the surrounding healthy tissue; (2) identifying malignant tissue within a region of formerly treated fibrotic tissue; and (3) guiding the surgeon in the identification of small metastatic lesions in the abdominal wall that require an immediate change in therapeutic approach.
To obtain these goals, we have previously developed a highly promising contrast agent based on the beneficial characteristics of single-domain antibodies (sdAb) and the near-infrared fluorophore s775z, that can effectively highlight tumors by binding to carcinoembryonic antigen (CEA). This protein is overexpressed in various abdominal tumors, including colorectal and pancreatic cancers. The current project aims to fulfill all requirements to start clinical testing of the fluorescent CEA-targeting sdAb. We will produce the fluorescent CEA-targeting sdAb under current Good Manufacturing Practice (cGMP) standards and complete all administrative requirements to initiate a subsequent phase I trial. When the current project is finalized, we will be fully ready to test our fluorescent CEA-targeting sdAb in the clinic to aid the surgeon in intra-operative decision-making in the surgical treatment of colorectal cancer.
This project started on 1/10/2023 and ends on 30/9/2026.
This project has received funding from Kom Op Tegen Kanker.
HORIZON-EIC-2021-PATHFINDEROPEN CoDaFlight
The project CoDaFlight (Colouring the Dark in Fluorescence light) is the development of a next-generation imaging platform capable of revealing in real-time new and more accurate information related to a patient’s body and its diseases through an innovative time-domain fluorescence imaging (tdFLI) technology. Real-time imaging of fluorescence lifetime, deep into the patient, permits the unlocking of rich information, where today’s medical imaging systems remain in the dark. The objectives of CoDaFlight are to develop the technological foundations that are needed to enable real-time in vivo tdFLI in medical practice and to integrate these foundations into a complete working imaging system.
The Consortium responsible for executing the project is: Universitätsmedizin Göttingen, Germany; FORTH, Greece; Université of Bourgogne, France; Universitetet i Bergen, Norway; Vrije Universiteit Brussel, Belgium.
The project started on October 1, 2022 and is ending 30 September 2026
The project has received in 2022 funding from the HORIZON-EIC-2021- PATHFINDEROPEN program under number ID 101047263
FWO SBO NLITESurgery
NLITESurgery aims to investigate novel intraoperative imaging applications based on time-domain fluorescence lifetime imaging (tdFLI) that will surpass the more traditional fluorescence guided surgery field by increasing image specificity and providing new information on (patho)physiological processes. More specifically, we propose to conceive a unique video-rate tdFLI system that will boost the applications of the clinically available fluorescent dye ICG, or that can be used in combination with dedicated nanobody-based targeted fluorescent tracers. Ultimately, this will improve surgical accuracy, influence decision-making on a per patient basis and reduce surgically- induced side effects.
To this end, a multidisciplinary consortium composed of surgeons, medical scientists, imaging specialists, engineers, and chemists was established. The consortium will be headed by Prof. Lahoutte and brings together experts with international reputation in electronic engineering of fluorescence cameras (lifetime sensing by Prof. Kuijk and Prof. Ingelberts, ETRO, VUB and backside illumination processing by imec with Dr. Sabuncuoglu Tezcan), fluorescent tracer development (Prof. Hernot, ICMI, VUB; Prof. van Leeuwen, LUMC, NL) and oncologic surgery (Prof. De Rooster, Small Animal Surgery, UGent; Prof. De Sutter, Gynaecology, UZBrussel). The consortium will be advised by experts in precision surgery, surgical robots, cGMP production of biologicals, sensor development and visualization solutions.
The project started on October 6th, 2021 and will end on September 31th, 2025
IOF POC: Open clinical system for Fluorescence Guided Surgery
Today, fluorescence lifetime (FLT) based systems are not available for open-surgery and similar macroscopic applications. The newly developed and patented CAPS-based sensor will unlock the FLT potential, because it will be able to handle fluorescence lifetime, in real time, in the most sensitive manner. As such it can disrupt the utility of intraoperative fluorescence imaging because it is independent of imaging parameters such as concentration and depth, provides additional characterization of signals, and can provide contrast between two fluorophores emitting at the same wavelength (multiplexing).
Our aim is to develop the Proof-of-Concept (PoC) instrument for the FGS application, the instrument needs to be developed from the base technology, and the application needs to be shown in concept for the first time. We therefore build a prototype of an open-surgery FLT camera instrument in a quality housing with all the necessary electronics, LASER, cooling and connectors and apply it to practice.
PI: Prof. Maarten Kuijk, Dr. Ir. Hans Ingelberts
The project started on January 1st, 2020 and ends on December 30th, 2021
Funding partners: IOF
STK: Peroperative ex vivo cancer margin detection using fluorescence labelled
single-domain antibodies
In the current project we propose to facilitate the intraoperative assessment of the surgical margin status by means of rapid ex vivo staining of resected tissues using fluorescent-labelled nanobodies (Nb’s). Patients diagnosed with tumours of the breast, prostate, pancreas and head and neck, planned for surgical removal will be included. These patients will receive tumorectomy as standard of care. Immediately after surgery, the freshly resected tumour will be cut into slices and incubated with a fluorescent Nb. After incubation, the stained tissue will be assessed for co-localization of fluorescence and malignant tissue, both macro- and microscopically and additional immunohistochemistry will be performed. Eventually, sensitivity, specificity and clinical applicability of the technique will be calculated based on the gold standard of histopathology.
The project started on March 1st, 2021 and ends on February 28th, 2024.
KOTK: Confirming the applicability of the anti-EGFR Nanobodies for fluorescence guided surgery in canine and human head and neck cancer, a translational trial
For the majority of solid cancers, surgical removal remains the mainstay of anti-cancer therapy with the aim to completely remove all tumoural tissue. An important outcome measure is therefore the absence of residual cancer cells after surgery. The use of a fluorescent contrast agent that highlights the tumour cells in real-time may facilitate resection of solid cancers.
The epidermal growth factor receptor (EGFR), overexpressed in various types of malignancies, in particular in head and neck cancer such as squamous cell carcinoma (SCC), has been demonstrated to be a relevant biomarker to distinguish malignant from healthy cells, resulting in high tumour-to-background contrasted images during real-time fluorescenceguided surgery (FGS). In this project, we will use Nanobodies (Nb’s) against EGFR to serve as ligands because the much smaller Nb’s have better kinetics and tissue penetration as compared to monoclonal antibodies, which are currently used for FGS. Furthermore, we will perform clinical trials in companion dogs with naturally occurring cancer, a relevant but still severely underexploited preclinical model for advancing human patient anti-cancer strategies. When fluorescent contrast agents can successfully identify malignant cells in dogs with cancer, it is likely that these agents will succeed in clinical trials in human patients with a similar tumour type.
The proposed project aims to assess whether anti-EGFR Nb’s have potential to allow for early diagnosis in cases of head and neck cancer, to improve the surgical outcome by achieving negative surgical margins because of intra-operative margin delineation and disseminated tumour cell identification. Consequently, FGS using anti-EGFR Nb’s might have the potential to reduce the need for adjuvant therapy and associated morbidity, and to increase survival time in patients with head and neck cancer. To this end, three strategies will be tested. In a first step, topically applied fluorescence-labelled anti- EGFR Nb’s will be applied on fresh tissue biopsies of human and equivalent canine head and neck cancers to demonstrate whether topical ex vivo application of anti-EGFR fluorescent-labelled Nb’s can successfully identify EGFR-positive head and neck cancer at the time of diagnosis in dogs and humans. In addition, the fluorescence-labelled anti-EGFR Nb’s will be topically applied to the wound bed in dogs after surgical removal of a head and neck malignancy to screen for remaining fluorescence, which would be indicative of residual cancer cells. Furthermore, dogs with head and neck SCC will receive intravenous anti-EGFR Nb 1 hour before the planned surgical removal of the malignancy. Fluorescence-guided surgery will be performed in which fluorescence intensities of tumour and adjacent tissues will be compared in vivo during surgery as well as after surgical removal of the tumour. In all three steps studies, biopsies will be taken and processed for immunohistochemistry (IHC) and the expression and distribution of EGFR will be compared to the fluorescence data. This proof-of-concept project will reveal preliminary data on sensitivity and specificity of the novel contrast agent to identify malignant tissue that overexpresses EGFR.
This information is of paramount importance: if the anti-EGFR Nb’s can indeed differentiate between malignant and normal tissue, the investments to produce the Nb’s under Good Manufacturing Practice (GMP) are justified and clinical trials in humans can be designed. The project will be executed by a consortium comprised of complementary teams covering expertise in veterinary oncologic surgery, clinical head and neck surgery, clinical pathology, and development of fluorescent contrast agents, all ensuring also the clinical translational relevance of this project.
The project started on December 1st, 2021 and ends on November 30th, 2024.
Title: FWO – Senior - Single-sensor methods for fluorescence-guided surgery
Fluorescence imaging is making headways in surgical assistance, lighting up blood flow, lymph nodes or even specific tissues such as tumors or nerves in an effort to guide a surgeon in procedures and decisions. There exist systems that can image the natural fluorescence of tissues and other systems to image injected fluorescence contrast in the infrared. These systems have to be built with multiple camera’s to capture both the fluorescence and the natural color image. We propose to research a novel method in which, using pulsed multispectral illumination in combination with a nanosecond camera with one single image sensor, the natural color image, and the natural fluorescence, and the infrared fluorescence can be imaged simultaneously. This will be possible by separating the spectral components of the illumination on a nanosecond timescale and imaging these components selectively with the nanosecond camera. In this project we wish to take the first step towards this innovative method and demonstrate it a first time to incite follow-up fundamental and applied research.
The project started on Januari 1st, 2022 and ends on December 31st, 2025.
Imaging with Hybrid Nanobody-Tracer for Improved Clinical Decision-Making in Colorectal Cancer (INDiCCaTe).
Patients with locally advanced rectal cancer are treated with neoadjuvant therapy prior to surgical resection. 20% of those patients show a complete response after neoadjuvant therapy and could enter a watch-and-wait policy, where surgery, which is often associated with considerable morbidity, is omitted. Within INDiCCaTe, we aim to achieve better clinical decision-making for (colo)rectal cancer patients through implementation of advanced imaging strategies leading to a more clinical- and cost-effective deployment of the treatment options. Hereto, we steadily progress to develop a single, innovative, easy-to-use and affordable tumour-specific imaging agent exploitable for both nuclear and fluorescent imaging and preclinically validate it. With implementation at different moments in the treatment plan, patients eligible for omitting surgery will be better selected, and in case of surgical/ endoscopic resection, the surgeon will be better equipped to obtain a more complete resection of the tumor.
The project started on November 1, 2022 and ends on October 31, 2026.
IOF related project funding to develop a cGMP compliant sdAb (Accelerator and Cancer Bequest)
Part of NLITE is our vision is to achieve better clinical decision-making through advanced imaging strategies leading to a more clinical- and cost-effective deployment of treatment options. Before we can proceed towards clinical valorization, we need cGMP-grade sdAb that can be administered to patients. Unfortunately, cGMP-production generally creates a bottleneck for the clinical translation of molecular tracers as it is difficult to find financial recourses for this essential development step. We have started this project to the optimalization of an in-house cGMP production process and set-up of a quality assurance system for subsequent release of cGMP produced compounds. By lowering the development costs and focusing more on the patient studies themselves, we can position ourselves in a more competitive position for future funding and drastically accelerate the initiation of clinical trials.
The project started on October 1, 2022 and ends on September 30, 2023.