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

神经母细胞瘤的颜色编码手术：开发双 PET/近红外荧光成像探针，实现肿瘤从诊断到切除的可视化

• 批准号: MR/T005491/1
• 负责人: Stefano Giuliani
• 金额: $ 23.47万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT005491%2F1
• 关键词: Colour; coded; surgery; Neuroblastoma; developing

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.

神经母细胞瘤是儿童中第二常见的实体肿瘤，在英国每年约有100名新儿童受到影响。治疗神经母细胞瘤的主要外科挑战之一是能够切除整个肿瘤。这一点尤其困难，因为神经母细胞瘤在腹腔和/或胸腔的后部具有弥漫性生长的特点，而且肿瘤与主要血管紧密附着，增加了严重出血的风险。因此，有必要开发一种肿瘤特异性检测策略，以帮助外科医生轻松地显示活的肿瘤细胞与应该保留的正常解剖结构。我们假设，开发一种单一的方法来跟踪活跃的肿瘤细胞从诊断到后续，包括他们在手术中的实时可视化，将是这种侵袭性儿童癌症治疗的重大进步。在过去的十年里，两种成像方式已经证明了改变我们治疗癌症的方式的潜力。首先，正电子发射断层扫描(PET)已成为监测癌症治疗反应的有力工具。其次，近红外荧光(NIRF)成像已被证明是一种非常有前途的图像引导的肿瘤组织切除技术，因为它有助于在手术中实时、高分辨率地勾勒出肿瘤边缘。我们的目标是选择性地标记神经母细胞瘤细胞，以便在治疗的不同阶段和术中使用荧光(NIRF)进行全身扫描(PET)。简而言之，在项目的头18个月，我们将把一种常用的神经母细胞瘤特异性抗体(抗GD2单抗)与市场上不同的荧光分子偶联。这将使我们了解荧光是否可以选择性地附着在体外的神经母细胞瘤细胞上(目标1)。然后，我们将在成熟的神经母细胞瘤动物模型中进行一系列实验，以确认在体内从不同器官可视化神经母细胞瘤的可能性(目标2)。作为这一目标的一部分，我们将基于荧光成像(NIRF)对小鼠的肿瘤进行外科解剖。下一步(目标3)将创建第二个标记，以通过PET扫描可视化肿瘤。如果上述目标成功，我们将能够注册知识产权，并与专业制备和制造单抗的公司联系，按照良好的制造规范(GMP)方法开发双标记NIRF/PET单抗。在项目的第二个18个月，我们将进行临床试验，以测试双NIRF/PET探头在人体中的安全性和有效性(目标4)。学术合作伙伴和合作者提供的专业知识和设施非常适合开发该项目(请参阅支持案例)。在项目结束时，我们希望有一种新的分子可以用于治疗儿童神经母细胞瘤。这将在有效监测不同治疗过程中活跃的肿瘤细胞、更容易手术切除和更客观地评估肿瘤残留以及更好的术后长期随访方面带来巨大的优势。新的NIRF/PET分子还将允许个性化手术治疗神经母细胞瘤。由于外科医生对肿瘤进行了更好的可视化，患者将接受不那么广泛和更有针对性的手术，并发症的风险也会更低。这可能是这种恶性疾病手术进展的一个里程碑，可以提高存活率，减少残留疾病的机会。

项目成果

Evaluating the Development Status of Fluorescence-Guided Surgery (FGS) in Pediatric Surgery Using the Idea, Development, Exploration, Assessment, and Long-Term Study (IDEAL) Framework.

• DOI: 10.3390/children10040689
• 发表时间: 2023-04-05
• 期刊: Children (Basel, Switzerland)

Fluorescence-Guided Surgery (FGS) during a Laparoscopic Redo Nissen Fundoplication: The First Case in Children.

• DOI: 10.3390/children9070947
• 发表时间: 2022-06-24
• 期刊: CHILDREN-BASEL
• 影响因子: 2.4
• 作者: Paraboschi, Irene;Privitera, Laura;Loukogeorgakis, Stavros;Giuliani, Stefano
• 通讯作者: Giuliani, Stefano

Near-InfraRed PhotoImmunoTherapy (NIR-PIT) for the local control of solid cancers: Challenges and potentials for human applications.

• DOI: 10.1016/j.critrevonc.2021.103325
• 发表时间: 2021-05
• 期刊: Critical reviews in oncology/hematology
• 作者: Paraboschi I;Turnock S;Kramer-Marek G;Musleh L;Barisa M;Anderson J;Giuliani S
• 通讯作者: Giuliani S

Dynamic Changes in Microvascular Density Can Predict Viable and Non-Viable Areas in High-Risk Neuroblastoma.

• DOI: 10.3390/cancers15030917
• 发表时间: 2023-02-01
• 期刊: Cancers
• 影响因子: 5.2

Novel Treatments and Technologies Applied to the Cure of Neuroblastoma.

• DOI: 10.3390/children8060482
• 发表时间: 2021-06-07
• 期刊: Children (Basel, Switzerland)
• 作者: Paraboschi I;Privitera L;Kramer-Marek G;Anderson J;Giuliani S
• 通讯作者: Giuliani S