Focused Ultrasound Delivers Targeted Immune Cells To Metastatic Brain Tumors
Menée in vitro et à l'aide d'un modèle murin de cancer du sein métastatique, cette étude montre que les ultrasons focalisés peuvent faciliter la migration des lymphocytes NK du sang vers le cerveau pour traiter des métastases cérébrales
Natural killer (NK) cells are cytotoxic lymphocytes involved in innate immunity. NK-92, a human NK cell line, may be targeted to tumor-associated antigens in solid malignancies where it exhibits antitumor efficacy, but its clinical utility for treating brain tumors is limited by an inability to cross the blood-brain barrier (BBB). We investigated the potential for focused ultrasound (FUS) to deliver targeted NK-92 cells to the brain using a model of metastatic breast cancer. HER-2-expressing human breast tumor cells were implanted into the brain of nude rats. The NK-92-scFv(FRP5)-zeta cell line expressing a chimeric HER-2 antigen receptor was transfected with super-paramagnetic iron oxide nanoparticles before intravenous injection, before and following BBB-disruption using focused ultrasound (551.5 kHz focused transducer, 0.33 MPa average peak rarefaction pressure) in the presence of a microbubble contrast agent. Baseline and post-treatment 1.5T and 7T MR imaging was performed, and histology used to identify NK-92 cells post-mortem. Contrast-enhanced MRI showed reproducible and consistent BBB-disruption. 7T MR images obtained at 16 hours post-treatment revealed a significant reduction in signal indicating the presence of iron-loaded NK-92 cells at the tumor site. The average ratio of NK-92 to tumor cells was 1:100 when NK cells were present in the vasculature at the time of sonication, versus 2:1000 and 1:1000 when delivered after sonication and without BBB-disruption, respectively. Our results offer a preclinical proof-of-concept that FUS can improve the targeting of immune cell therapy of brain metastases.