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Intramucosal Inoculation of Squamous Cell Carcinoma Cells in Mice for Tumor Immune Profiling and Treatment Response Assessment
Published on: April 22, 2019
Immuno-PET imaging based radioimmunotherapy in head and neck squamous cell carcinoma model
In Ho Song1, Youn Noh2, Junhye Kwon2
1Division of RI Convergence Research, Research Institute of Radiological and Medical Sciences (RIRAMS), Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul, Republic of Korea.
Abstract:
The epidermal growth factor receptor (EGFR) is one of the most comprehensively studied molecular targets in head and neck squamous cell carcinoma (HNSCC). However, inherent and acquired resistance are serious problems and are responsible for limited clinical efficacy and tumor recurrence. In this study, we evaluated the feasibility of immuno-positron emission tomography (PET) imaging and radioimmunotherapy (RIT) with 64Cu-/177Lu-PCTA-cetuximab in cetuximab-resistant SNU-1066 HNSCC xenografted model. The cellular uptake of 64Cu/177Lu-3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA)-cetuximab showed good correlation with western blot and flow cytometry analysis in EGFR expression level of various HNSCC cells. 177Lu-PCTA-cetuximab selectively killed cetuximab-resistant SNU-1066 cells in vitro. 64Cu-/177Lu-PCTA-cetuximab specifically accumulated in SNU-1066 tumor and those uptakes were peaked at 48 h and 7 day, respectively in biodistribution, PET and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. RIT with single dose of 177Lu-PCTA-cetuximab exhibited significant tumor regression and markedly reduced 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) uptake, compared to other groups. Proliferation index were dramatically decreased and apoptotic index increased in RIT group. These results suggest that a diagnostic and therapeutic convergence radiopharmaceutical, 64Cu-/177Lu-PCTA-cetuximab has the potential of target selection using immuno-PET imaging and targeted therapy by RIT in EGFR expressing cetuximab-resistant HNSCC tumors.
Insights
This study shows that 64Cu/177Lu-PCTA-cetuximab can be used for imaging and radioimmunotherapy (RIT) in EGFR-expressing, cetuximab-resistant head and neck squamous cell carcinoma (HNSCC) models, demonstrating tumor regression.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Epidermal growth factor receptor (EGFR) is a key target in head and neck squamous cell carcinoma (HNSCC).
- Resistance to EGFR inhibitors like cetuximab limits treatment efficacy and leads to tumor recurrence.
- Novel therapeutic and diagnostic strategies are needed for cetuximab-resistant HNSCC.
Purpose of the Study:
- To evaluate the feasibility of immuno-PET imaging and radioimmunotherapy (RIT) using 64Cu/177Lu-PCTA-cetuximab in a cetuximab-resistant HNSCC model.
- To assess the diagnostic potential of 64Cu-PCTA-cetuximab for target selection.
- To evaluate the therapeutic efficacy of 177Lu-PCTA-cetuximab for RIT.
Main Methods:
- Developed and characterized 64Cu/177Lu-PCTA-cetuximab for imaging and RIT.
- Assessed EGFR expression correlation using western blot and flow cytometry.
- Evaluated in vitro cytotoxicity and in vivo tumor targeting, biodistribution, and therapeutic effects in SNU-1066 HNSCC xenografts.
- Utilized immuno-PET and SPECT/CT imaging for tumor visualization and quantification.
Main Results:
- Cellular uptake of 64Cu/177Lu-PCTA-cetuximab correlated with EGFR expression levels.
- 177Lu-PCTA-cetuximab demonstrated selective killing of cetuximab-resistant HNSCC cells in vitro.
- Significant tumor accumulation of 64Cu/177Lu-PCTA-cetuximab was observed in vivo, peaking at 48 hours and 7 days.
- Single-dose RIT with 177Lu-PCTA-cetuximab resulted in significant tumor regression and reduced 18F-FDG uptake.
- RIT treatment decreased proliferation and increased apoptosis in tumor tissues.
Conclusions:
- 64Cu/177Lu-PCTA-cetuximab shows potential as a theranostic agent for EGFR-expressing, cetuximab-resistant HNSCC.
- Immuno-PET imaging can effectively guide targeted therapy selection.
- RIT with 177Lu-PCTA-cetuximab offers a promising therapeutic strategy for resistant HNSCC tumors.
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