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Published on: December 15, 2010
Focused ultrasound delivers targeted immune cells to metastatic brain tumors
Ryan Alkins1, Alison Burgess, Milan Ganguly
1Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
Abstract:
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. HER2-expressing human breast tumor cells were implanted into the brain of nude rats. The NK-92-scFv(FRP5)-zeta cell line expressing a chimeric HER2 antigen receptor was transfected with superparamagnetic 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 posttreatment 1.5T and 7T MR imaging was done, 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 posttreatment 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 2:1,000 and 1:1,000 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.
Insights
Focused ultrasound (FUS) with microbubbles can temporarily open the blood-brain barrier (BBB), enabling targeted delivery of natural killer (NK) cells for brain tumor treatment. This preclinical study demonstrates improved NK-92 cell accumulation at brain metastases.
Area of Science:
- Oncology
- Immunology
- Biomedical Engineering
Background:
- Natural killer (NK) cells are crucial for innate immunity and show antitumor potential.
- The blood-brain barrier (BBB) restricts the efficacy of NK cell therapies in brain tumors.
- Targeting NK-92 cells to brain tumors requires overcoming BBB limitations.
Purpose of the Study:
- To investigate focused ultrasound (FUS) as a method to enhance the delivery of targeted NK-92 cells across the BBB to brain metastases.
- To evaluate the efficacy of FUS-mediated BBB disruption in improving NK cell accumulation at HER2-expressing brain tumors.
Main Methods:
- Utilized a rat model of HER2-positive breast cancer brain metastases.
- Administered NK-92 cells engineered with a HER2-targeting chimeric antigen receptor and magnetic nanoparticles.
- Disrupted the BBB using FUS with a microbubble contrast agent before and during NK cell administration.
- Assessed NK cell delivery and tumor site accumulation using MRI and histology.
Main Results:
- Focused ultrasound reliably and reproducibly disrupted the BBB.
- MRI confirmed the presence of iron-loaded NK-92 cells at the tumor site 16 hours post-treatment.
- NK cell targeting to the tumor was significantly enhanced when delivered during FUS-induced BBB opening compared to other delivery methods.
Conclusions:
- Focused ultrasound represents a promising strategy for improving the brain-targeting of immune cell therapies for brain metastases.
- This preclinical study provides proof-of-concept for FUS-mediated delivery of NK cells to brain tumors.
- FUS may enhance the clinical utility of NK cell-based immunotherapies for central nervous system malignancies.
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