Low response rates in solid tumors including head and neck cancers (HNCs) have been attributed to failure of the drug to reach its intended target. However, investigation of drug delivery has been limited due to difficulties in measuring concentrations in the tumor and the ability to localizing drugs in human tissues. Factors determining intratumoral antibody distribution in primary tumor and metastatic lymph nodes have not been well-studied in human patients. To address this challenge, we propose to leverage fluorescently labeled antibodies to investigate antibody delivery into HNCs.
To this end, we have conducted a first-in-human clinical trial to assess the delivery of panitumumab-IRDye800 in HNCs. Twenty-two patients enrolled in this study received intravenous administration of panitumumab-IRDye800 at multiple subtherapeutic doses: (1) 0.06mg/kg, (2) 0.5 mg/kg, (3) 1 mg/kg, (4) 50 mg flat dose, (5) 25 mg flat dose. To quantify the antibody delivery, fresh tumor samples were procured and the amount of antibody in the tumor was quantified as ng/mg of tissue, which was then correlated with tumor characteristics. Immunohistochemistry of multiple protein markers, including EGFR, ERG, cytokeratin, Ki67, alpha-smooth muscle actin, etc., have been implemented in serial sections of primary tumors and metastatic lymph nodes. A quantitative image analysis pipeline was developed to analyze these IHC images and score the staining on both global and local scale. A predictive model was built to identify the most important predictors for antibody penetration from pharmacological factors, tumor pathophysiological factors, and tumor microenvironmental factors.
BACKGROUND: Presence of lymph node (LN) metastasis is considered the most important prognostic factor in patients with head and neck cancer, yet intraoperative identification of metastatic LNs is considered challenging. We propose the near-infrared fluorescently labeled epidermal growth factor receptor (EGFR) antibody panitumumab-IRDye800 for intraoperative metastatic LN identification.
METHODS: Patients were injected 2-5 days before surgery with panitumumab-IRDye800 (0.5 or 1.0 mg/kg). On the day of surgery, (excised) LN samples were evaluated on high sensitivity fluorescence imaging systems (SurgVision (SurgOptix), PINPOINT (Novadaq), and Pearl imager and Odyssey CLx (LI-COR Biosciences). Location and intensity of the fluorescence signal was correlated to the location of tumor as defined on the hematoxylin and eosin staining by the pathologist, and the EGFR expression pattern. We calculated the sensitivity, specificity, positive and negative predictive values of panitumumab-IRdye800 for metastatic LN identification.
RESULTS: We thus far included 9/27 patients in our ongoing phase I trial. 244 LNs were removed intraoperatively of which 8 were tumor-positive. Fluorescence imaging of panitumumab-IRdye800 revealed 236 true-negative nodes (not fluorescent, not tumor-positive), 8 true-positive nodes (fluorescent, tumor-positive), 0 false-positive nodes (fluorescent, not tumor-positive) and 0 false-negative nodes (not fluorescent, tumor-positive) resulting in a sensitivity of 100%, a specificity of 100%, and a positive and negative predictive value of 100% and 100%, respectively.
CONCLUSION: Preliminary results from our ongoing study suggest panitumumab-IRDye800 can identify metastatic LNs. Upon trial progression, if findings remain constant, it can open a whole new era for intraoperative metastatic LN identification.
Access to the requested content is limited to institutions that have purchased or subscribe to SPIE eBooks.
You are receiving this notice because your organization may not have SPIE eBooks access.*
*Shibboleth/Open Athens users─please
sign in
to access your institution's subscriptions.
To obtain this item, you may purchase the complete book in print or electronic format on
SPIE.org.
INSTITUTIONAL Select your institution to access the SPIE Digital Library.
PERSONAL Sign in with your SPIE account to access your personal subscriptions or to use specific features such as save to my library, sign up for alerts, save searches, etc.