Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography
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Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography
Published on: February 17, 2022
Nourhan Shalaby1, Ying Xia2, John J Kelly2
1Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. nshalaby@uwo.ca.
Abstract:
Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([18F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients.
Insights
Engineered HER2-targeted CAR-NK cells show promise for ovarian cancer treatment. Non-invasive PET imaging using the NIS reporter gene effectively tracks these chimeric antigen receptor (CAR) natural killer (NK) cells in vivo.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR) T cell therapies show potential but face challenges like variable responses and high costs.
- Developing off-the-shelf allogeneic CAR natural killer (CAR-NK) cells offers an alternative to autologous CAR T cells.
- Non-invasive imaging is crucial for tracking CAR cell therapy efficacy and patient outcomes.
Purpose of the Study:
- To engineer HER2-targeted CAR-NK cells expressing the PET reporter gene NIS for ovarian cancer therapy.
- To evaluate the therapeutic efficacy of these CAR-NK cells in a HER2 ovarian cancer mouse model.
- To assess the feasibility of non-invasive PET imaging for monitoring CAR-NK cell distribution and persistence.
Main Methods:
- Genetically modified NK-92 cells to express HER2-CAR, Antares (bioluminescence reporter), and NIS (PET reporter).
- Engineered HER2 ovarian cancer cells to express Firefly luciferase (Fluc) for bioluminescence imaging.
- Conducted in vitro cytotoxicity assays and in vivo studies in mice, utilizing bioluminescence and PET imaging.
Main Results:
- CAR-NK cells demonstrated significantly enhanced cytotoxicity against HER2+ cancer cells in vitro.
- In vivo, CAR-NK cell treatment led to reduced tumor burden and prolonged survival in mice.
- Longitudinal bioluminescence imaging confirmed stable CAR-NK cell presence, and PET imaging detected significantly higher signals in NIS-expressing CAR-NK cell-treated mice.
Conclusions:
- HER2-targeted CAR-NK cells exhibit significant therapeutic potential against aggressive ovarian cancer.
- Co-expression of the NIS reporter gene enables effective non-invasive PET imaging of CAR-NK cells.
- This approach facilitates monitoring of CAR-NK cell therapy, paving the way for clinical translation.
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