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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. Cancer Res; 73(6); 1892–9. ©2012 AACR.

Necrosis is a form of cell death that is often associated with highly aggressive forms of cancer, is of prognostic value in treatment planning. Mass Spectrometry (MS) is a highly sensitive analytic platform capable of providing a molecular profile of cancer on the basis of mass to charge (m/z) ratio of tissue constituent molecules. MS analysis of ex vivo tissue slices from metastatic murine xenograft tumors from LM2-4 cell line with Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) allowed direct comparisons with histology images to determine the molecular profile of necrotic tissues. The necrotic tissue is characterized by the presence of a ceramide absent from the viable cancer regions. The spatial distribution of this ion fully correlated to necrotic areas from pathology in additional independent tumor samples examined. The same ion was detected from in situ necrotic tissue using tissue aerosols generated by hand-held ablation probes coupled to evaporative ionization interface in only a few seconds of sampling. These developments further establish MS as a novel tool for rapid pathology that is highly complementary to current histology based methods widely used in characterization of cancer in both imaging mode (to provide spatial information on cancer border) and profiling mode (to provide information on cancer type and subtype); all based on unique molecular profile associated with each cancer type and subtype. Current efforts in creating cancer molecular profile libraries will facilitate translation. Citation Format: Arash Zarrine-Afsar, Bindesh Shrestha, Alessandra Tata, Michael Woolman, Manuela Ventura, Nicholas Bernards, Milan Ganguly, Howard Ginsberg, Jinzi Zheng, Emma Bluemke. Rapid detection of necrosis in breast cancer with ex vivo and in situ mass spectrometry analysis methods [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 741. doi:10.1158/1538-7445.AM2017-741