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

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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.