울산의대 / 김석영, 류진숙*
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.
Affiliation
Seog-Young Kim 1, Hyunsu Soh 1, Jin Hwa Jung 1, Eun Hye Cho 1, Hyori Kim 1, Ji-Min Ju 1, Joong Hyuk Sheen 1, Sang Ju Lee 1, Seung Jun Oh 1, Sang-Jin Lee 1, Junho Chung 1, Jin-Sook Ryu 1
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.).
편집위원
CAR-T 세포는 다양한 악성종양의 치료에 효과를 나타낼수 있는 세포치료제이며 세포치료제가 생체내에서 표적이 되는 종양에 축적여부 확인은 해당세포치료제의 효과를 예측하는데 매우 중요한 요소임. 해당연구은 실험동물 연구를 통해 직접 및 간접리포터유전자 영상기법을 이용하여 생체내 CAR-T 세포의 PET 영상화를 보여준 매우 우수한 연구임. 분자영상 및 핵의학 영상 관련 임상가 및 세포치료술에 관심을 가진 연구자에게 흥미를 끌 것 기초 연구로 생각됨.
2024-03-29 15:25:09