Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography

Nourhan Shalaby; Ying Xia; John J Kelly; Rafael Sanchez-Pupo; Francisco Martinez; Matthew S Fox; Jonathan D Thiessen; Justin W Hicks; Timothy J Scholl; John A Ronald

doi:10.1007/s00259-024-06722-w

Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography

Eur J Nucl Med Mol Imaging. 2024 May 9. doi: 10.1007/s00259-024-06722-w. Online ahead of print.

Authors

Nourhan Shalaby¹, Ying Xia², John J Kelly², Rafael Sanchez-Pupo², Francisco Martinez², Matthew S Fox^{3

4}, Jonathan D Thiessen^{2

5

4}, Justin W Hicks^{2

3

5}, Timothy J Scholl^{6

2

7}, John A Ronald^{6

2

3}

Affiliations

¹ Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. nshalaby@uwo.ca.
² Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
³ Lawson Health Research Institute, London, ON, Canada.
⁴ Saint Joseph's Health Care, London, ON, Canada.
⁵ Lawson Cyclotron and Radiochemistry Facility, London, ON, Canada.
⁶ Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁷ Ontario Institute for Cancer Research, London, ON, Canada.

PMID: 38722382
DOI: 10.1007/s00259-024-06722-w

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.

Keywords: Bioluminescence imaging; Cellular therapy; Chimeric antigen receptor (CAR); HER2; Natural killer (NK) cells; Positron emission tomography.

Grants and funding

1UH2EB028907-01/NH/NIH HHS/United States