Intraoperative identification of metastatic lesions is challenging due to unpredictable locations and coverage
by normal tissue. Intraoperative molecular imaging (IMI) uses targeted radioisotopes and/or fluorophores to
guide surgeons to cancer tissue and distinguish tumor margins from normal surrounding tissue. Radioactive
isotopes and near-infrared (NIR) fluorophores complement each other in dual-labeled probes by providing both
depth of detection (radioisotope) and visual delineation of tumor borders (fluorophore) with common clinically
used handheld detectors. Metastatic osteosarcoma is one type of cancer that could benefit from IMI for improved
resection given the difficulty of identifying lesions and tumor margins.
Osteosarcoma (OS) is the most common primary bone cancer in children and adolescents with an overall 5-
year-survival rate of 60-70% for localized disease and only 20% for metastatic disease. Macroscopically
complete resection of primary and metastatic lesions is associated with longer survival, making intraoperative
detection critical. Ninety percent of OS metastases occur in the lungs, though preoperative CT misses small
pulmonary metastases. Further, lesions are difficult to detect below the lung surface, necessitating an invasive
thoracotomy to palpate the lesions, which unfortunately can still be missed. Fluorescent agents have shown
promise in aiding OS metastasis resection but have limited depth of detection. There is a critical need for
methods to improve the completeness of metastatic tumor resection and decrease the invasiveness of surgery.
GD2 is a tumor antigen that is weakly expressed in normal CNS tissue and melanocytes but highly
overexpressed in multiple cancers, including neuroblastoma and primary, recurrent, and metastatic OS. The
FDA-approved chimeric antibody, dinutuximab, targets GD2 for maintenance therapy in neuroblastoma. Our
group recently constructed DTPA[111In]-dinutuximab-IRDye800CW (111In-dinutuximab-IR800), composed of
dinutuximab to target GD2, DTPA[111In] to detect primary neuroblastoma at up to 5 cm depth with a handheld
gamma probe, and IRDye800CW to visualize the cancer with a handheld NIR camera. After promising
neuroblastoma xenograft studies in mice, 111In-dinutuximab-IR800 is poised for clinical translation for a primary
GD2-expressing cancer but has not yet been evaluated for metastatic disease.
We hypothesize that 111In-dinutuximab-IR800 can be developed for clinical use in primary and
metastatic pediatric tumor resection. In Aim 1, we will optimize consistency of manufacturing, and study its
pharmacology, toxicology, and stability profile to enable clinical use. In Aim 2, we will test its ability to detect OS
metastases in vivo. The long-term goal of this project is to translate this IMI agent into clinical trials for use in
resection of neuroblastoma, metastatic OS, and other GD2-expressing tumors. We will use results from these
aims to prepare an IND and design an early phase clinical trial for intraoperative use of 111In-dinutuximab-IR800
in the surgical resection of primary neuroblastoma and osteosarcoma metastases.