Project Grant F32CA287961

INTRAOPERATIVE MOLECULAR IMAGING OF METASTATIC OSTEOSARCOMA WITH 111IN-DINUTUXIMAB-IR800 - 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.