title: Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival.
abstract: Malignant brain tumors have a dismal prognosis, with residual tumor remaining after surgery necessitating adjuvant chemoradiotherapy. The blood-brain barrier hinders many chemotherapeutic agents, resulting in modest treatment efficacy. We previously demonstrated that targeted natural killer (NK)-92 cells could be delivered to desired regions of the brain using MRI-guided focused ultrasound and Definity microbubbles. Targeted NK-92 cells have advantages over many systemic therapies including their specific cytotoxicity to malignant cells (particularly those expressing the target antigen), ability to spare healthy cells, and being unaffected by efflux channels.
  
  
  
  We investigated whether longitudinal treatments with targeted NK-92 cells, focused ultrasound, and microbubbles could slow tumor growth and improve survival in an orthotopic HER2-amplified rodent brain tumor model using a human breast cancer line as a prototype. The HER2 receptor, involved in cell growth and differentiation, is expressed by both primary and metastatic brain tumors. Breast cancers with HER2 amplification have a higher risk of CNS metastasis and poorer prognosis.
  
  
  
  Early intensive treatment with targeted NK-92 cells and ultrasound improved survival compared with biweekly treatments or either treatment alone. The intensive treatment paradigm resulted in long-term survival in 50% of subjects.
  
  
  
  Many tumor proteins could be exploited for targeted therapy with the NK-92 cell line; combined with the mounting safety evidence for transcranial ultrasound, these results may soon be translatable to a highly targeted treatment option for patients with brain tumors.
authors.affiliation: Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada (R.A., A.B., K.H.); Medical Biophysics, University of Toronto, Toronto, Ontario, Canada (R.A., R.K., K.H.); Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada (R.K.); Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany (W.S.W.).
authors.forename: Ryan
authors.initials: R
authors.lastname: Alkins
authors.affiliation: Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada (R.A., A.B., K.H.); Medical Biophysics, University of Toronto, Toronto, Ontario, Canada (R.A., R.K., K.H.); Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada (R.K.); Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany (W.S.W.).
authors.forename: Alison
authors.initials: A
authors.lastname: Burgess
authors.affiliation: Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada (R.A., A.B., K.H.); Medical Biophysics, University of Toronto, Toronto, Ontario, Canada (R.A., R.K., K.H.); Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada (R.K.); Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany (W.S.W.).
authors.forename: Robert
authors.initials: R
authors.lastname: Kerbel
authors.affiliation: Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada (R.A., A.B., K.H.); Medical Biophysics, University of Toronto, Toronto, Ontario, Canada (R.A., R.K., K.H.); Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada (R.K.); Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany (W.S.W.).
authors.forename: Winfried S
authors.initials: WS
authors.lastname: Wels
authors.affiliation: Physical Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada (R.A., A.B., K.H.); Medical Biophysics, University of Toronto, Toronto, Ontario, Canada (R.A., R.K., K.H.); Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada (R.K.); Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany (W.S.W.).
authors.forename: Kullervo
authors.initials: K
authors.lastname: Hynynen
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001932:Brain Neoplasms / Q000473:pathology* / Q000628:therapy; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000378:metabolism; D045423:Microbubbles / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014464:Ultrasonic Therapy / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: MRIgFUS; breast cancer; focused ultrasound; immune cell therapy
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