A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer
Open accessAbstract
Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.
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Proof of concept for synthetic biomarkers has been shown in humans by identifying residual cancer after surgery with a protease-activated fluorescent probe.
“and identification of residual cancer after surgery in humans through a protease-activated fluorescent probe.91”
From Early detection of pancreatic cancer (2020) · cites this paper as [91]
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“been tested in a mouse-human phase I co-clinical trial, offering the first promising human data for this technique [260].”
MethodActivatable fluorescence: From small molecule to nanoparticle
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“Protease-activated imaging agents utilize disease biochemistry to generate localized contrast and are a promising class of probes for in vivo visualization of cancer (14, 15).”
BackgroundEmerging Fluorescent Molecular Tracers to Guide Intra-Operative Surgical Decision-Making
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BackgroundTargeted Optical Imaging Agents in Cancer: Focus on Clinical Applications
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“(d) Representative ex vivo fluorescence images of resected normal humanmuscle and sarcoma along with corresponding histology ((c) and (d) reprinted with the permission from [89]).”
BackgroundInfluentialNear-Infrared Fluorescent Probes for the Detection of Cancer-Associated Proteases
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“A small number of proof-of-principle studies in humans have been reported (19, 20, 22), but the efficacy of these techniques for reducing re-excision rates in BCS has not been determined.”
BackgroundActivity-Based Diagnostics: An Emerging Paradigm for Disease Detection and Monitoring
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Peptide probes for proteases – innovations and applications for monitoring proteolytic activity
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“The Lumicell (LUM) Imaging System (Lumicell, Wellesley, MA) includes LUM015, a novel PEGylated proteaseactivated far-red fluorescent imaging agent [21]; the LUM optical head, a hand-held probe, and sterile cover used to excite LUM015 and collect real-time fluorescent recordings; and software for image analysis.”
InfluentialFang, B., Shen, Y., Peng, B., Bai, H., Wang, L., Zhang, J., Hu, W., Fu, L., Zhang, W., Li, L., et al. (2022) · Angewandte Chemie International Edition · doi:10.1002/anie.202207188 · Cited by 86 · see citing works
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Small-Molecule Lanthanide Complexes Probe for Second Near-Infrared Window Bioimaging
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Cyanine Conjugate‐Based Biomedical Imaging Probes
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Peptides for optical medical imaging and steps towards therapy
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“…of tissue perfusion, fluorescence-guided surgery, 21,22 sentinel lymph-node mapping and general lymphography, 20,25–27 detection of prema-lignant/malignant lesions (ClinicalTrials.gov; NCT02113202 and NCT01972373), and tumor identification and margin detection, 24,28–30 among other applications.”
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“LUM015 is a PEGylated protease-activated fluorescent imaging probe [94].”
BackgroundImage‐guided tumor surgery: The emerging role of nanotechnology
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“Examples include the FDA-approved Lymphoseek®, a technetium 99mTc-dextran conjugate for sentinel lymph nodes (SLN) identification that has shown persistent SLN accumulation for at least 24 h [40], a polyethyleneglycol-bound (PEGylated) protease activatable fluorescent probe that is in a phase 1 clinical trial [41] and…”
Molecular imaging: design mechanism and bioapplications
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Protease-Sensitive Nanomaterials for Cancer Therapeutics and Imaging
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Protease Specificity: Towards In Vivo Imaging Applications and Biomarker Discovery
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Intraoperative Fluorescence Guidance for Breast Cancer Lumpectomy Surgery
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Deployment and exploitation of nanotechnology nanomaterials and nanomedicine
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Advances in fluorescent-image guided surgery
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“LUM015 was injected intravenously into 15 patients with either invasive ductal carcinoma or soft tissue sarcoma and was well tolerated with no adverse pharmacological activity (36).”
BackgroundMethodInfluentialOptical Surgical Navigation for Precision in Tumor Resections
Harmsen, S., Teraphongphom, N. T., Tweedle, M. F., Basilion, J. P., & Rosenthal, E. L. (2017) · Molecular Imaging and Biology · doi:10.1007/s11307-017-1054-1 · Cited by 56 · see citing works
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“Important new clinical imaging tools are also arriving including a cathespinactivated PEG-peptide conjugate (LUM015) for intraoperative imaging of residual disease [47] that is currently undergoing clinical evaluation in breast cancer [48].”
BackgroundRadiation Therapy for Soft Tissue Sarcoma
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Optimization of a Protease Activated Probe for Optical Surgical Navigation
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Advanced Photosensitizer Activation Strategies for Smarter Photodynamic Therapy Beacons
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Advances and challenges in precision imaging
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Molecular probes for fluorescence image-guided cancer surgery
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BackgroundMagnetically Actuated Protease Sensors for in Vivo Tumor Profiling
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Advances in Diagnostic and Intraoperative Molecular Imaging of Pancreatic Cancer
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Intraoperative Fluorescence‐Guided Surgery in Head and Neck Squamous Cell Carcinoma
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Fluorescence-Guided Surgery in the Surgical Treatment of Gliomas: Past, Present and Future
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- Authors
- Whitley, M. J., Cardona, D. M., Lazarides, A. L., Spasojevic, I., Ferrer, J. M., Cahill, J., Lee, C.-L., Snuderl, M., Blazer, D. G., Hwang, E. S., Greenup, R. A., Mosca, P. J., Mito, J. K., Cuneo, K. C., Larrier, N. A., O’Reilly, E. K., Riedel, R. F., Eward, W. C., Strasfeld, D. B., Fukumura, D., Jain, R. K., Lee, W. D., Griffith, L. G., Bawendi, M. G., Kirsch, D. G., & Brigman, B. E.
- Affiliations
- Duke Medical Center (US)
- Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
- Lumicell (United States) (US)
- Harvard University (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- Kirsch, David G.
- Brigman, Brian E.
- ORCID
- Whitley, Melodi Javid
- Cardona, Diana M.
- Lazarides, Alexander L.
- Lee, Chang-Lung
- Snuderl, Matija
- Blazer, Dan G.
- Hwang, E. Shelley
- Greenup, Rachel A.
- Mosca, Paul J.
- Mito, Jeffrey K.
- Cuneo, Kyle C.
- O’Reilly, Erin K.
- Riedel, Richard F.
- Eward, William C.
- Fukumura, Dai
- Griffith, Linda G.
- Bawendi, Moungi G.
- Kirsch, David G.
- Brigman, Brian E.
- Venue
- Science Translational Medicine
- Published
- 2016-01-06
- Volume
- 8
- Issue
- 320
- Pages
- 320ra4-320ra4
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC4794335
- OpenAlex
- W2240104466
- Cited by
- 296
- References
- 40
- Citations by year
- 2026: 24 · 2025: 18 · 2024: 20 · 2023: 23 · 2022: 32 · 2021: 43 · 2020: 36 · 2019: 18 · 2018: 33 · 2017: 31 · 2016: 17 · 2015: 1
- FWCI
- 13.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- PMC
- Funders
- American Society of Clinical Oncology Advanced Clinical Research Award
- NIH (#T32GM007171)
- National Cancer Institute Small Business Innovation Research (#1U43CA165024)
- National Center for Advancing Translational Science (#UL1TR001117)
- Duke Comprehensive Cancer Center Support (5P30-CA-014236-38)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Optical Imaging and Spectroscopy Techniques
- Keywords
- tumor imaging, soft tissue sarcoma, breast cancer, local recurrence, intraoperative tumor detection, tumor bed, pharmacokinetics, lysine labeling
- MeSH terms
- Animals, Breast Neoplasms, Diagnostic Imaging, Disease Models, Animal, Female, Fluorescent Dyes, Humans, Injections, Intravenous, Neoplasms, Peptide Hydrolases, Sarcoma, Tissue Distribution, Mice, Metabolome
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