Colour-coded surgery in Neuroblastoma: developing a dual PET/Near-Infrared Fluorescence Imaging probe to visualise tumour from diagnosis to resection

Neuroblastoma is the second most common solid tumour in children, and it affects around 100 new children a year in the UK. One of the main surgical challenges in the treatment of neuroblastoma is to be able to remove the entire tumour. This is particularly difficult because of the characteristic diffuse growth of neuroblastoma in the posterior part of the abdominal and/or thoracic cavities and the fact the tumour is strictly adherent to major blood vessels increasing the risk of severe bleeding. Therefore, there is the need to develop a tumour-specific detection strategy that could assist surgeons in providing easy visualisation of viable tumour cells versus normal anatomical structures that should be preserved.
We hypothesise that developing a single way to track active tumour cells from diagnosis to follow-up, including their real-time visualisation during surgery, will be a major advance in the treatment of this aggressive paediatric cancer.
Over the past decade, two imaging modalities have demonstrated the potential of transforming the way we treat cancer. First, positron emission tomography (PET) has become a powerful tool in monitoring the cancer response to treatments. Second, near-infrared fluorescence (NIRF) imaging has proven to be a very promising technique for the image-guided resection of tumour tissue, as it facilitates the real-time, high-resolution delineation of tumour margins during surgery.
We aim to selectively label neuroblastoma cells so they can be visualised with a whole-body scan (PET) during the different phases of treatment and intraoperatively with the use of fluorescence (NIRF).
Briefly, in the first 18 months of the project, we will conjugate a commonly used specific antibody against neuroblastoma (anti-GD2 monoclonal antibody-mAb) with different fluorescent molecules available on the market. This will allow us to understand if fluorescence can be selectively attached to neuroblastoma cells in vitro (Objective 1). Then we will run a series of experiments in well-established animal models of neuroblastoma to confirm the possibility of visualising neuroblastoma from different organs in vivo (objective 2). As part of this objective, we will carry on surgical dissections of the tumour in mice based on fluorescent imaging (NIRF). The next step (objective 3) will be to create a second labelling to visualise the tumour with a PET scan. If the above objectives are successful, we will be able to register the intellectual property and to link with companies specialised in the preparation and engineering of monoclonal antibodies to develop the dual labelled NIRF/PET monoclonal antibodies following Good Manufacturing Practice (GMP) methods. In the second 18 months of the project, we will run a clinical trial to test the safety and efficacy of the dual NIRF/PET probe in humans (objective 4).
The expertise and facilities provided by the academic partner and collaborators are excellent to develop this project (see Case for Support).
At the end of the project, we expect to have a novel molecule that can be used in the cure of children with neuroblastoma. This will bring huge advantages in term of effective monitoring of active tumour cells during different treatments, easier surgical resection with a more objective assessment of tumour residuals, and better long term post-surgical follow-up. The novel NIRF/PET molecule will also allow personalised surgery to treat neuroblastoma. As a consequence of better visualisation of the tumour by the surgeon, patients will receive less extensive and more targeted surgery with less risk for complications. This can be a milestone in the progress of surgery for this malignant disease and can lead to increase survival and reduce the chance of residual disease.

Neuroblastoma (NB) is the second most common solid cancer in children, and it affects around 100 new children per year in the UK. One of the main challenges in the treatment of neuroblastoma is to be able to remove the residual tumour following multiple medical treatments. Radical excision of neuroblastoma is challenging because it widely infiltrates into the deepest parts of the abdominal and/or chest cavities.
Colour-coded surgery is one of the most promising and needed surgical innovations that could significantly increase the survival in solid tumours. This project aims to develop a dual-labelled PET/NIRF anti-GD2 mAbs probe specific for neuroblastoma. This novel probe will allow for the first time to track active neuroblastoma cells from diagnosis to follow-up, including the real-time visualisation during surgery and at histology.
We will run 18 months of laboratory-based experiments (objectives 1, 2 and 3) to prove it is feasible to double label anti-GD2 monoclonal antibodies with an effective near-infrared fluorescence (NIRF) probe and a PET tracer (e.g. Zirconium-89). We will test this novel probe in vitro and in vivo in a series of experiments based on established animal models of neuroblastoma. If successful, we will then design and run a phase 1/2 clinical trials in humans to test the validity of the dual PET-GD2-mAbs-NIRF probe manufactured in a GMP-compliant way (objective 4).
The main benefit of this research will be for the children affected by neuroblastoma as the expected results will be essential to achieve the first personalized surgical therapy in the field. Surgical outcomes will improve as surgeons will be able to see better the tumour during the operation. This will improve the chances to resect the entire tumour, and will also reduce the risk of damaging vital tissues often adherent to cancer. Patients will hopefully achieve better long-term survival rate with less surgical complications and less local recurrence of the disease.

The successful development of a specific dual PET/NIRF probe will benefit children affected by neuroblastoma in the next 3-5 years. This novel probe could be used from diagnosis to surgery and it will allow better assessment of the disease response to chemotherapy through repeated PET/CT scans. Then the same probe will be used to light up with green fluorescence the tumour during the surgery (colour-coded surgery). The colour-coded surgery will enable surgeons to better visualise cancer cells during the resection of intrabdominal, thoracic and neck neuroblastoma making the operation easier. Fluorescence and live optical imaging will allow surgeons to precisely identify tumour margins during resection, ensuring that no healthy tissue is removed and that no residual tumour tissue is overlooked. This will allow less invasive and extensive surgery with the benefit of an early recovery and fewer risks for the patients. If successful, this will have a significant impact on improving survival and surgical outcomes in children with neuroblastoma who will be the main beneficiaries of this novel technology. As a direct consequence, this technique will become part of international protocols to treat neuroblastoma and will be used to treat more effectively other types of cancer in adult and children.
The commercial sector will strongly benefit from the partnership with our academic consortium developing this project. We are planning to involve key medical device and high-tech companies at an early stage of the project to be able to partner in the development of novel: monoclonal antibodies, optical and nuclear medicine imaging, surgical instruments, robotic surgery and artificial intelligence.
The first step in our pathway to impact will be licensing the intellectual property allowing for accelerated translation into clinical applications through industry collaboration. There is an established pathway at UCL for securing of intellectual property derived from research grants in which the technology transfer office (UCL Business) will support patent applications and revenue sharing agreements with funders as well as working in partnerships to secure industrial collaboration.
Robotic surgery and artificial intelligence are rapidly emerging fields in surgery. The current surgical robot is equipped with a camera capable of visualising fluorescence. Our project will support and develop significant innovations to better visualise normal organs and tissues from tumour or scar/necrotic tissues. At the moment this is not possible as the surgeon has to remove every single millimetre of abnormal tissue around the tumour even if that will end up being just scar tissue at histology. The reason is that it is not possible for the surgeon to differentiate viable versus non-viable (scar or necrotic) tumour intraoperatively without the use of serial biopsies that are time-consuming and often inaccurate. The possibility to enhance surgeon's eyes to have a microscopic vision during resection in cancer surgery is the best dream for every surgeon. Then, if we will be able to add together enhanced vision, precision of movements and a computer able to recognise different tissues in real time, we will have developed the ideal surgeon on the planet.
This novel translational project is an important clinical unmet need in the field of paediatric oncology. Great Ormond Street Hospital has one of the largest paediatric cancer programs in the world and it is keen to fully implement the novel findings from this project acquiring a PET/CT in the next 2-3 years. In addition, we are in contact with the hospital charity to explore the possibility to buy a surgical robot that could support and develop these new technologies together with us.