| Autor: |
Sunil Singhal, Gavin Wright, Jason D. Lickliter, Evgeniy Eruslanov, Charles W. Bradley, A.J. Matthew Egan, Matthew Bogyo, Edward J. Delikatny, John C. Kucharczuk, John T. Santini, Eric Bensen, Charuhas Desphande, Alix Segil, Neil T. Sullivan, Ashley Chang, Bilal Nadeem, Elizabeth Bernstein, Feredun S. Azari, David E. Holt, Gregory T. Kennedy |
| Rok vydání: |
2023 |
| Popis: |
Purpose:Fluorescence-guided surgery using tumor-targeted contrast agents has been developed to improve the completeness of oncologic resections. Quenched activity–based probes that fluoresce after covalently binding to tumor-specific enzymes have been proposed to improve specificity, but none have been tested in humans. Here, we report the successful clinical translation of a cathepsin activity–based probe (VGT-309) for fluorescence-guided surgery.Experimental Design:We optimized the specificity, dosing, and timing of VGT-309 in preclinical models of lung cancer. To evaluate clinical feasibility, we conducted a canine study of VGT-309 during pulmonary tumor resection. We then conducted a randomized, double-blind, dose-escalation study in healthy human volunteers receiving VGT-309 to evaluate safety. Finally, we tested VGT-309 in humans undergoing lung cancer surgery.Results:In preclinical models, we found highly specific tumor cell labeling that was blocked by a broad spectrum cathepsin inhibitor. When evaluating VGT-309 for guidance during resection of canine tumors, we found that the probe selectively labeled tumors and demonstrated high tumor-to-background ratio (TBR; range: 2.15–3.71). In the Phase I human study, we found that VGT-309 was safe at all doses studied. In the ongoing Phase II trial, we report two cases in which VGT-309 localized visually occult, non-palpable tumors (TBRs = 2.83 and 7.18) in real time to illustrate its successful clinical translation and potential to improve surgical management.Conclusions:This first-in-human study demonstrates the safety and feasibility of VGT-309 to label human pulmonary tumors during resection. These results may be generalizable to other cancers due to cathepsin overexpression in many solid tumors. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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