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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
Direct and Indirect Chimeric Antigen Receptor T-Cell Imaging with PET/MRI in a Tumor Xenograft Model
Seog-Young Kim1, Hyunsu Soh1, Jin Hwa Jung1
1From the Convergence Medicine Research Center (S.Y.K., H.S., J.H.J., H.K.) and Department of Nuclear Medicine (E.H.C., Sang Ju Lee, S.J.O., J.S.R.), Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Research Institute, National Cancer Center, Gyeonggi-do, Republic of Korea (J.M.J., J.H.S., Sang-Jin Lee); and Department of Biomedical Sciences, Seoul National University, Seoul, Republic of Korea (J.C.).
Abstract:
Background Chimeric antigen receptor (CAR) T cells are a promising cancer therapy; however, reliable and repeatable methods for tracking and monitoring CAR T cells in vivo remain underexplored. Purpose To investigate direct and indirect imaging strategies for tracking the biodistribution of CAR T cells and monitoring their therapeutic effect in target tumors. Materials and Methods CAR T cells co-expressing a tumor-targeting gene (anti-CD19 CAR) and a human somatostatin receptor subtype 2 (hSSTr2) reporter gene were generated from human peripheral blood mononuclear cells. After direct labeling with zirconium 89 (89Zr)-p-isothiocyanatobenzyl-desferrioxamine (DFO), CAR T cells were intravenously injected into immunodeficient mice with a CD19-positive and CD19-negative human tumor xenograft on the left and right flank, respectively. PET/MRI was used for direct in vivo imaging of 89Zr-DFO-labeled CAR T cells on days 0, 1, 3, and 7 and for indirect cell imaging with the radiolabeled somatostatin receptor-targeted ligand gallium 68 (68Ga)-DOTA-Tyr3-octreotide (DOTATOC) on days 6, 9, and 13. On day 13, mice were euthanized, and tissues and tumors were excised. Results The 89Zr-DFO-labeled CAR T cells were observed on PET/MRI scans in the liver and lungs of mice (n = 4) at all time points assessed. However, they were not visualized in CD19-positive or CD19-negative tumors, even on day 7. Serial 68Ga-DOTATOC PET/MRI showed CAR T cell accumulation in CD19-positive tumors but not in CD19-negative tumors from days 6 to 13. Notably, 68Ga-DOTATOC accumulation in CD19-positive tumors was highest on day 9 (mean percentage injected dose [%ID], 3.7% ± 1.0 [SD]) and decreased on day 13 (mean %ID, 2.6% ± 0.7) in parallel with a decrease in tumor volume (day 9: mean, 195 mm3 ± 27; day 13: mean, 127 mm3 ± 43) in the group with tumor growth inhibition. Enhanced immunohistochemistry staining of cluster of differentiation 3 (CD3) and hSSTr2 was also observed in excised CD19-positive tumor tissues. Conclusion Direct and indirect cell imaging with PET/MRI enabled in vivo tracking and monitoring of CAR T cells in an animal model. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bulte in this issue.
Insights
This study demonstrates PET/MRI imaging for tracking CAR T cells in vivo. Indirect imaging successfully visualized CAR T cell accumulation in tumors, correlating with therapeutic effects.
Area of Science:
- Oncology
- Immunotherapy
- Medical Imaging
Background:
- Chimeric antigen receptor (CAR) T cell therapy shows promise in cancer treatment.
- Reliable in vivo tracking and monitoring methods for CAR T cells are underdeveloped.
- Investigating imaging strategies is crucial for assessing CAR T cell biodistribution and therapeutic efficacy.
Purpose of the Study:
- To evaluate direct and indirect imaging techniques for tracking CAR T cell biodistribution.
- To monitor the therapeutic impact of CAR T cells within target tumors.
- To assess the utility of PET/MRI in conjunction with reporter genes and radiotracers.
Main Methods:
- Generated CAR T cells co-expressing anti-CD19 CAR and human somatostatin receptor subtype 2 (hSSTr2) reporter gene.
- Directly labeled CAR T cells with 89Zr-DFO for PET/MRI imaging.
- Administered 68Ga-DOTATOC for indirect imaging of hSSTr2 expression in mice bearing CD19-positive and CD19-negative tumors.
Main Results:
- 89Zr-DFO-labeled CAR T cells were detected in liver and lungs but not in tumors.
- 68Ga-DOTATOC PET/MRI revealed CAR T cell accumulation specifically in CD19-positive tumors.
- 68Ga-DOTATOC uptake in tumors decreased in parallel with tumor volume reduction, indicating therapeutic effect.
Conclusions:
- Direct PET/MRI imaging with 89Zr-DFO did not visualize CAR T cells within tumors.
- Indirect imaging using 68Ga-DOTATOC effectively tracked CAR T cell accumulation in target tumors.
- PET/MRI combined with reporter gene strategies enables in vivo monitoring of CAR T cell therapy efficacy.
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