Abstract
Neuroblastoma resection represents a major challenge in pediatric surgery, because of the high risk of complications. Fluorescence-guided surgery (FGS) could lower this risk by facilitating discrimination of tumor from normal tissue and is gaining momentum in adult oncology. Here, we provide the first molecular-targeted fluorescent agent for FGS in pediatric oncology, by developing and preclinically evaluating a GD2-specific tracer consisting of the immunotherapeutic antibody dinutuximab-beta, recently approved for neuroblastoma treatment, conjugated to near-infrared (NIR) fluorescent dye IRDye800CW. We demonstrated specific binding of anti-GD2-IRDye800CW to human neuroblastoma cells in vitro and in vivo using xenograft mouse models. Furthermore, we defined an optimal dose of 1 nmol, an imaging time window of 4 days after administration and show that neoadjuvant treatment with anti-GD2 immunotherapy does not interfere with fluorescence imaging. Importantly, as we observed universal, yet heterogeneous expression of GD2 on neuroblastoma tissue of a wide range of patients, we implemented a xenograft model of patient-derived neuroblastoma organoids with differential GD2 expression and show that even low GD2 expressing tumors still provide an adequate real-time fluorescence signal. Hence, the imaging advancement presented in this study offers an opportunity for improving surgery and potentially survival of a broad group of children with neuroblastoma.
Highlights
Neuroblastoma (NB) is the most common extracranial solid tumor occurring in children[1]
In vivo validation was performed in NB cell line derived xenograft mouse models using the Pearl Trilogy Small Animal imaging system and Quest Spectrum imaging system. (b) Representative histogram and accumulative data of anti-GD2-IRDye800CW staining by flow cytometry on KCNR and HT-29 cells, compared to unstained cells. c) Representative histogram and accumulative data of anti-GD2-IRDye800CW staining on KCNR cells compared to CD52-IRDye-800CW staining. (b, c) n = 3 independent experimental repeats
Fluorescence-guided surgery (FGS) with tumor surface antigen specific probes is increasingly implemented in adult oncology[11,25], its application in pediatric oncology is still scarce
Summary
Neuroblastoma (NB) is the most common extracranial solid tumor occurring in children[1]. (b) Representative histogram (left panel) and accumulative data (right panel) of anti-GD2-IRDye800CW staining by flow cytometry on KCNR and HT-29 cells, compared to unstained cells. C) Representative histogram (left panel) and accumulative data (right panel) of anti-GD2-IRDye800CW staining on KCNR cells compared to CD52-IRDye-800CW staining. (d) Representative images using the surgical imaging device of mice bearing subcutaneous human KCNR-derived tumors, acquired 1 day (left panel) and 4 days (right panel) after administration of 3 ascending doses of anti-GD2-IRDye800CW. Patients with remnant NB are currently successfully treated with anti-GD2 immunotherapy after s urgery[14,15] We conjugated this clinical grade antibody to the near-infrared (NIR) fluorophore IRDye800CW to explore its potential as a FGS probe for NB in preclinical settings
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