Wendy Metz

A Phase 2 Study of 99mTc-Tilmanocept in the Detection of Sentinel Lymph Nodes in Melanoma and Breast Cancer

BackgroundSeveral 99mTc-labeled agents that are not approved by the U.S. Food and Drug Administration are used for lymphatic mapping. A new low-molecular-weight mannose receptor–based, reticuloendothelial cell-directed, 99mTc-labeled lymphatic imaging agent, 99mTc-tilmanocept, was used for lymphatic mapping of sentinel lymph nodes (SLNs) from patients with primary breast cancer or melanoma malignancies. This novel molecular species provides the basis for potentially enhanced SLN mapping reliability.MethodsIn a prospectively planned, open-label phase 2 clinical study, 99mTc-tilmanocept was injected into breast cancer and cutaneous melanoma patients before intraoperative lymphatic mapping. Injection technique, preoperative lymphoscintigraphy (LS), and intraoperative lymphatic mapping with a handheld gamma detection probe were performed by investigators per standard practice.ResultsSeventy-eight patients underwent 99mTc-tilmanocept injection and were evaluated (47 melanoma, 31 breast cancer). For those whom LS was performed (55 patients, 70.5%), a 99mTc-tilmanocept hot spot was identified in 94.5% of LS patients before surgery. Intraoperatively, 99mTc-tilmanocept identified at least one regional SLN in 75 (96.2%) of 78 patients: 46 (97.9%) of 47 in melanoma and 29 (93.5%) of 31 in breast cancer cases. Tissue specificity of 99mTc-tilmanocept for lymph nodes was 100%, displaying 95.1% mapping sensitivity by localizing in 173 of 182 nodes removed during surgery. The overall proportion of 99mTc-tilmanocept-identified nodes that contained metastatic disease was 13.7%. Five procedure-related serious adverse events occurred, none related to 99mTc-tilmanocept.ConclusionsOur results demonstrate the safety and efficacy of 99mTc-tilmanocept for use in intraoperative lymphatic mapping. The high intraoperative localization and lymph node specificity of 99mTc-tilmanocept and the identification of metastatic disease within the nodes suggest SLNs are effectively identified by this novel mannose receptor–targeted molecule.

γ-Tilmanocept, a New Radiopharmaceutical Tracer for Cancer Sentinel Lymph Nodes, Binds to the Mannose Receptor (CD206)

γ-Tilmanocept (99mTc-labeled-tilmanocept or [99mTc]-tilmanocept) is the first mannose-containing, receptor-directed, radiolabeled tracer for the highly sensitive imaging of sentinel lymph nodes in solid tumor staging. To elucidate the mannose-binding receptor that retains tilmanocept in this microenvironment, human macrophages were used that have high expression of the C-type lectin mannose receptor (MR; CD206). Cy3-labeled tilmanocept exhibited high specificity binding to macrophages that was nearly abolished in competitive inhibition experiments. Furthermore, Cy3-tilmanocept binding was markedly reduced on macrophages deficient in the MR by small interfering RNA treatment and was increased on MR-transfected HEK 293 cells. Finally, confocal microscopy revealed colocalization of Cy3-tilmanocept with the macrophage membrane MR and binding of labeled tilmanocept to MR+ cells (macrophages and/or dendritic cells) in human sentinel lymph node tissues. Together these data provide strong evidence that CD206 is a major binding receptor for γ-tilmanocept. Identification of CD206 as the γ-tilmanocept–binding receptor enables opportunities for designing receptor-targeted advanced imaging agents and therapeutics for cancer and other diseases.

Corrigendum to the inextricable axis of targeted diagnostic imaging and therapy: An immunological natural history approach [Nucl Med Biol 43 (2016) 215–225]

Corrigendum to the inextricable axis of targeted diagnostic imaging and therapy: An immunological natural history approach [Nucl Med Biol 43 (2016) 215–225] Frederick O. Cope⁎, Bonnie Abbruzzese, James Sanders, Wendy Metz, Kristyn Sturms, David Ralph, Michael Blue, Jane Zhang, Paige Bracci, Wiam Bshara, Spencer Behr, Toby Maurer, Kenneth Williams, Joshua Walker, Allison Beverly, Brooke Blay, Anirudh Damughatla, Mark Larsen, Courtney Mountain, Erin Neylon, Kaeli Parcel, Kapil Raghuraman, Kevin Ricks, Lucas Rose, Akhilesh Sivakumar, Nicholas Streck, Bryan Wang, Christopher Wasco, Amifred Williams, Larry S. Schlesinger , Abul Azad, Murugesan V.S. Rajaram, Wael Jarjour, Nicholas Young, Thomas Rosol , Michael McGrath

Abstract LB-216: Receptor targeted (CD206) Tc99m tilmanocept localization in sentinel nodes in breast cancer and melanoma is concordant with preoperative imaging and a reduction in missed disease

Purpose: Tilmanocept is wholly synthetic molecule composed of a dextran-10 backbone with both multiple mannose side moieties (for receptor biding) and DTPA (for chelation of divalent cations). Tilmanocept is designed as a high affinity ligand for the human mannose binding receptor (CD206) of reticuloendothelial cells (RECs), and more specifically, those RECs that reside in tumor-draining lymph nodes. Tilmanocept is designed to provide high sensitivity and specificity for intraoperative lymphatic mapping in melanoma, breast cancer, head/neck squamous cell carcinoma, and other solid tumors. This study was designed to evaluate the correlation of preoperative imaging using Tc99m tilmanocept and intraoperative tumor bed-adnexed node findings, along with metatstatic disease finding for Tc99m tilmaocept with its “truth” comparator, Lymphazurin. Results/Conclusions: The results of combined prospective phase 3 clinical trials in breast cancer and melanoma indicate that there is a near 99% correlation between the preoperative imaging (lymphoscintigraphy) based on the use of the CD206 targeted Tc99m tilmanocept and the intraoperative/surgical findings of tumor-adnexed lymph nodes. Additionally, these findings provide exceptional guidance for nodal extraction in contrast to the “truth” mapping agent Lymphazurin, where Tc99m provides a significantly lower failed detection rate leading to a ∼10 percent improved staging rate for breast cancer and mealnoma patients (less missed disease and appropriate post-surgical treatment program). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-216. doi:1538-7445.AM2012-LB-216