Investigation of HIFU-induced anti-tumor immunity in a murine tumor model

<p>Abstract</p> <p>Background</p> <p>High intensity focused ultrasound (HIFU) is an emerging non-invasive treatment modality for localized treatment of cancers. While current clinical strategies employ HIFU exclusively for thermal ablation of the target sites, biological responses associated with both thermal and mechanical damage from focused ultrasound have not been thoroughly investigated. In particular, endogenous danger signals from HIFU-damaged tumor cells may trigger the activation of dendritic cells. This response may play a critical role in a HIFU-elicited anti-tumor immune response which can be harnessed for more effective treatment.</p> <p>Methods</p> <p>Mice bearing MC-38 colon adenocarcinoma tumors were treated with thermal and mechanical HIFU exposure settings in order to independently observe HIFU-induced effects on the host's immunological response. <it>In vivo </it>dendritic cell activity was assessed along with the host's response to challenge tumor growth.</p> <p>Results</p> <p>Thermal and mechanical HIFU were found to increase CD11c+ cells 3.1-fold and 4-fold, respectively, as compared to 1.5-fold observed for DC injection alone. In addition, thermal and mechanical HIFU increased CFSE+ DC accumulation in draining lymph nodes 5-fold and 10-fold, respectively. Moreover, focused ultrasound treatments not only caused a reduction in the growth of primary tumors, with tumor volume decreasing by 85% for thermal HIFU and 43% for mechanical HIFU, but they also provided protection against subcutaneous tumor re-challenge. Further immunological assays confirmed an enhanced CTL activity and increased tumor-specific IFN-γ-secreting cells in the mice treated by focused ultrasound, with cytotoxicity induced by mechanical HIFU reaching as high as 27% at a 10:1 effector:target ratio.</p> <p>Conclusion</p> <p>These studies present initial encouraging results confirming that focused ultrasound treatment can elicit a systemic anti-tumor immune response, and they suggest that this immunity is closely related to dendritic cell activation. Because DC activation was more pronounced when tumor cells were mechanically lysed by focused ultrasound treatment, mechanical HIFU in particular may be employed as a potential strategy in combination with subsequent thermal ablations for increasing the efficacy of HIFU cancer treatment by enhancing the host's anti-tumor immunity.</p

Sound scattering by several zooplankton groups. II. Scattering models

Author Posting. © Acoustical Society of America, 1998. This article is posted here by permission of Acoustical Society of America for personal use, not for redistribution. The definitive version was published in Journal of the Acoustical Society of America 103 (1998): 236-253, doi:10.1121/1.421110.Mathematical scattering models are derived and compared with data from zooplankton from several gross anatomical groups—fluidlike, elastic shelled, and gas bearing. The models are based upon the acoustically inferred boundary conditions determined from laboratory backscattering data presented in part I of this series [Stanton et al., J. Acoust. Soc. Am. 103, 225–235 (1998)]. The models use a combination of ray theory, modal-series solution, and distorted wave Born approximation (DWBA). The formulations, which are inherently approximate, are designed to include only the dominant scattering mechanisms as determined from the experiments. The models for the fluidlike animals (euphausiids in this case) ranged from the simplest case involving two rays, which could qualitatively describe the structure of target strength versus frequency for single pings, to the most complex case involving a rough inhomogeneous asymmetrically tapered bent cylinder using the DWBA-based formulation which could predict echo levels over all angles of incidence (including the difficult region of end-on incidence). The model for the elastic shelled body (gastropods in this case) involved development of an analytical model which takes into account irregularities and discontinuities of the shell. The model for gas-bearing animals (siphonophores) is a hybrid model which is composed of the summation of the exact solution to the gas sphere and the approximate DWBA-based formulation for arbitrarily shaped fluidlike bodies. There is also a simplified ray-based model for the siphonophore. The models are applied to data involving single pings, ping-to-ping variability, and echoes averaged over many pings. There is reasonable qualitative agreement between the predictions and single ping data, and reasonable quantitative agreement between the predictions and variability and averages of echo data.This work was supported by the National Science Foundation Grant No. OCE-9201264, the U.S. Office of Naval Research Grant Nos. N00014-89-J-1729, N00014-95-1-0287, and N00014-94-1-0452, and the MIT/WHOI Joint Graduate Education Program

Effects of urban stream burial on organic matter dynamics and reach scale nitrate retention

Nitrogen (N) retention in streams is an important ecosystem service that may be affected by the widespread burial of streams in stormwater pipes in urban watersheds. We predicted that stream burial suppresses the capacity of streams to retain nitrate (NO3 −) by eliminating primary production, reducing respiration rates and organic matter availability, and increasing specific discharge. We tested these predictions by measuring whole-stream NO3 − removal rates using 15NO3 − isotope tracer releases in paired buried and open reaches in three streams in Cincinnati, Ohio (USA) during four seasons. Nitrate uptake lengths were 29 times greater in buried than open reaches, indicating that buried reaches were less effective at retaining NO3 − than open reaches. Burial suppressed NO3 − retention through a combination of hydrological and biological processes. The channel shape of two of the buried reaches increased specific discharge which enhanced NO3 − transport from the channel, highlighting the relationship between urban infrastructure and ecosystem function. Uptake lengths in the buried reaches were further lengthened by low stream biological NO3 − demand, as indicated by NO3 − uptake velocities 17-fold lower than that of the open reaches. We also observed differences in the periphyton enzyme activity between reaches, indicating that the effects of burial cascade from the microbial to the ecosystem scale. Our results suggest that stream restoration practices involving “daylighting” buried streams have the potential to increase N retention. Further work is needed to elucidate the impacts of stream burial on ecosystem functions at the larger stream network scale

Phase I clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion

<p>Abstract</p> <p>Background</p> <p>Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib.</p> <p>Methods</p> <p>We immunized women (n = 12) with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD) and a portion of the intracellular domain (ICD) of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day) was administered concurrently. Peripheral blood antibody and T cell responses were measured.</p> <p>Results</p> <p>This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%).</p> <p>Conclusions</p> <p>dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway.</p> <p>Trial registry</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00952692">NCT00952692</a></p

A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer

BACKGROUND: There is a continued need to develop more effective cancer immunotherapy strategies. Exosomes, cell-derived lipid vesicles that express high levels of a narrow spectrum of cell proteins represent a novel platform for delivering high levels of antigen in conjunction with costimulatory molecules. We performed this study to test the safety, feasibility and efficacy of autologous dendritic cell (DC)-derived exosomes (DEX) loaded with the MAGE tumor antigens in patients with non-small cell lung cancer (NSCLC). METHODS: This Phase I study enrolled HLA A2+ patients with pre-treated Stage IIIb (N = 4) and IV (N = 9) NSCLC with tumor expression of MAGE-A3 or A4. Patients underwent leukapheresis to generate DC from which DEX were produced and loaded with MAGE-A3, -A4, -A10, and MAGE-3DPO4 peptides. Patients received 4 doses of DEX at weekly intervals. RESULTS: Thirteen patients were enrolled and 9 completed therapy. Three formulations of DEX were evaluated; all were well tolerated with only grade 1–2 adverse events related to the use of DEX (injection site reactions (N = 8), flu like illness (N = 1), and peripheral arm pain (N = 1)). The time from the first dose of DEX until disease progression was 30 to 429+ days. Three patients had disease progression before the first DEX dose. Survival of patients after the first DEX dose was 52–665+ days. DTH reactivity against MAGE peptides was detected in 3/9 patients. Immune responses were detected in patients as follows: MAGE-specific T cell responses in 1/3, increased NK lytic activity in 2/4. CONCLUSION: Production of the DEX vaccine was feasible and DEX therapy was well tolerated in patients with advanced NSCLC. Some patients experienced long term stability of disease and activation of immune effector