EGFR-targeted intraoperative fluorescence imaging detects high-grade glioma with panitumumab-IRDye800 in a phase 1 clinical trial

Abstract

Rationale : First-line therapy for high-grade gliomas (HGGs) includes maximal safe surgical resection. The extent of resection predicts overall survival, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a highly expressed HGG biomarker. We evaluated the safety and feasibility of an anti-EGFR antibody, panitumuab-IRDye800, at subtherapeutic doses as an imaging agent for HGG. Methods : Eleven patients with contrast-enhancing HGGs were systemically infused with panitumumab-IRDye800 at a low (50 mg) or high (100 mg) dose 1-5 days before surgery. Near-infrared fluorescence imaging was performed intraoperatively and ex vivo , to identify the optimal tumor-to-background ratio by comparing mean fluorescence intensities of tumor and histologically uninvolved tissue. Fluorescence was correlated with preoperative T1 contrast, tumor size, EGFR expression and other biomarkers. Results : No adverse events were attributed to panitumumab-IRDye800. Tumor fragments as small as 5 mg could be detected ex vivo and detection threshold was dose dependent. In tissue sections, panitumumab-IRDye800 was highly sensitive (95%) and specific (96%) for pathology confirmed tumor containing tissue. Cellular delivery of panitumumab-IRDye800 was correlated to EGFR overexpression and compromised blood-brain barrier in HGG, while normal brain tissue showed minimal fluorescence. Intraoperative fluorescence improved optical contrast in tumor tissue within and beyond the T1 contrast-enhancing margin, with contrast-to-noise ratios of 9.5 ± 2.1 and 3.6 ± 1.1, respectively. Conclusions : Panitumumab-IRDye800 provided excellent tumor contrast and was safe at both doses. Smaller fragments of tumor could be detected at the 100 mg dose and thus more suitable for intraoperative imaging.

Development of a multi faceted platform containing a tetrazine, fluorophore and chelator: synthesis, characterization, radiolabeling, and immuno-SPECT imaging

“…Despite their prevalence in optical imaging probes, BODIPY dyes exhibit excitation and emission bands lying in the < 600 nm range, which is suboptimal for intraoperative imaging; therefore, future scaffold designs may consider integrating dyes that excite/emit in the near infrared (NIR) I (650–900 nm) or NIR II (1000–1500 nm) windows (Ariztia et al 2022 ; He et al 2018 ). For example, fluorophores such as IRDye800 (Rosenthal et al 2015 ; Zhou et al 2021 ) or cyanine dyes (e.g., Cy5.5 (Tsai et al 2018 ; Kang et al 2016 )) have been used (pre-)clinically, and will be considered when designing our next generation of multi-modal scaffolds.…”

EGFR-targeted fluorescent imaging using the da Vinci® Firefly™ camera for gallbladder cancer

“…EGFR-targeted fluorescent imaging has been tested in clinical trials for several types of cancer, including head and neck cancer [ 25 ], pancreatic cancer [ 26 ], glioblastoma and glioma [ 13 , 27 ], oral cancer [ 28 ], and lung cancer [ 13 ]. Fluorescence-guided surgical imaging using panitumumab, an EGFR antibody, conjugated to IRDye800 was used to detect gliomas in real time [ 29 ], demonstrating good tumor-to-background contrast ratio. The same antibody was used in a murine model of colorectal cancer for fluorescence-guided surgery with a strong fluorescent contrast [ 30 ].…”

Fluorescence Molecular Targeting of Colon Cancer to Visualize the Invisible

“…Marston et al studied panitumumab-IRDye800 in mice with subcutaneous CRC and found that the molecule resulted in a significantly higher TBR in all three models compared to a nonspecific IgG-IRDye800 [ 102 ]. This conjugate has been well evaluated in preclinical and clinical studies of head and neck cancer [ 103 , 104 , 105 , 106 ], pancreatic cancer [ 107 , 108 , 109 ], and brain cancer [ 110 , 111 ]. A study using cetuximab-IRDye800 for locally advanced rectal cancer (TRACT-II) is ongoing in the Netherlands (NCT04638036).…”