30 research outputs found

    A phase I oncolytic virus trial with vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 administered intratumorally and intravenously in uveal melanoma: safety, efficacy, and T cell responses

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    IntroductionMetastatic uveal melanoma (MUM) has a poor prognosis and treatment options are limited. These patients do not typically experience durable responses to immune checkpoint inhibitors (ICIs). Oncolytic viruses (OV) represent a novel approach to immunotherapy for patients with MUM.MethodsWe developed an OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-β) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNβ-TYRP1), and conducted a Phase 1 clinical trial with a 3 + 3 design in patients with MUM. VSV-IFNβ-TYRP1 was injected into a liver metastasis, then administered on the same day as a single intravenous (IV) infusion. The primary objective was safety. Efficacy was a secondary objective.Results12 patients with previously treated MUM were enrolled. Median follow up was 19.1 months. 4 dose levels (DLs) were evaluated. One patient at DL4 experienced dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). 4 patients had stable disease (SD) and 8 patients had progressive disease (PD). Interferon gamma (IFNγ) ELIspot data showed that more patients developed a T cell response to virus encoded TYRP1 at higher DLs, and a subset of patients also had a response to other melanoma antigens, including gp100, suggesting epitope spreading. 3 of the patients who responded to additional melanoma antigens were next treated with ICIs, and 2 of these patients experienced durable responses.DiscussionOur study found that VSV-IFNβ -TYRP1 can be safely administered via intratumoral (IT) and IV routes in a previously treated population of patients with MUM. Although there were no clear objective radiographic responses to VSV-IFNβ-TYRP1, dose-dependent immunogenicity to TYRP1 and other melanoma antigens was seen

    MeV-Stealth: A CD46-specific oncolytic measles virus resistant to neutralization by measles-immune human serum.

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    The frequent overexpression of CD46 in malignant tumors has provided a basis to use vaccine-lineage measles virus (MeV) as an oncolytic virotherapy platform. However, widespread measles seropositivity limits the systemic deployment of oncolytic MeV for the treatment of metastatic neoplasia. Here, we report the development of MeV-Stealth, a modified vaccine MeV strain that exhibits oncolytic properties and escapes antimeasles antibodies in vivo. We engineered this virus using homologous envelope glycoproteins from the closely-related but serologically non-cross reactive canine distemper virus (CDV). By fusing a high-affinity CD46 specific single-chain antibody fragment (scFv) to the CDV-Hemagglutinin (H), ablating its tropism for human nectin-4 and modifying the CDV-Fusion (F) signal peptide we achieved efficient retargeting to CD46. A receptor binding affinity of ~20 nM was required to trigger CD46-dependent intercellular fusion at levels comparable to the original MeV H/F complex and to achieve similar antitumor efficacy in myeloma and ovarian tumor-bearing mice models. In mice passively immunized with measles-immune serum, treatment of ovarian tumors with MeV-Stealth significantly increased overall survival compared with treatment with vaccine-lineage MeV. Our results show that MeV-Stealth effectively targets and lyses CD46-expressing cancer cells in mouse models of ovarian cancer and myeloma, and evades inhibition by human measles-immune serum. MeV-Stealth could therefore represent a strong alternative to current oncolytic MeV strains for treatment of measles-immune cancer patients

    Human Factor Quantitative Analysis Based on OHFAM and Bayesian Network

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    Hf-Nd isotopic variability in mineral dustfrom Chinese and Mongolian deserts:implications for sources and dispersal

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    Mineral dust provenances are closely related to the orogenic processes which may have distinct Hf-Nd isotopic signatures. Here we report the clay-sized (,2 mm) Hf-Nd isotope data from Asian dust sources to better constrain the source and transport dynamics of dust deposition in the North Pacific. Our results show that there is a more positive radiogenic Hf isotopic composition with clay-sized fractions than the corresponding bulk sample and a decoupling of the Hf-Nd couplets in the clay formation during the weathering process. The clay-sized Hf-Nd isotopic compositions of the desert samples from the Sino-Korean-Tarim Craton (SKTC) are different from those of the Gobi and deserts from the Central Asian Orogeny Belt (CAOB) due to varying tectonic and weathering controls. The Hf-Nd isotopic compositions of dust in the North Pacific central province (NPC) match closely with those from the Taklimakan, Badain Jaran and adjacent Tengger deserts, implying that the NPC dust was mainly transported from these potential sources by the westerly jet. Our study indicates that dusts from the CAOB Gobi deserts either didn&rsquo;t arrive in NPC or were quantitatively insignificant, but they were likely transported to the North Pacific margin province (NPM) by East Asian winter monsoon.</p

    Carbonate leaching processes in the Red Clay Formation, Chinese Loess Plateau: Fingerprinting East Asian summer monsoon variability during the late Miocene and Pliocene

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    High-resolution variations in carbonate minerals from the Jiaxian Red Clay section, located at the northern limit of the present East Asian summer monsoon (EASM) on Chinese Loess Plateau were quantified using Fourier transform infrared spectroscopy. We analyzed a large quantity of sediments dated from the late Miocene to Pliocene (8.2-2.6 Ma). The carbonates in this interval show high-frequency variations alternating between leached and calcareous horizons. The low carbonate contents and high values of magnetic susceptibility and high Rb/Sr ratios were found in the leached zones, a pattern that is consistent with that observed in the overlying Quaternary loess-paleosol sequences. This pattern suggests that East Asian Monsoon (EAM) rainwater enhanced leaching and accumulation processes of carbonate minerals in the Red Clay Formation in a way similar to the loess-paleosol sequence. Seven alternating leached and calcareous zones are identified, suggesting oscillations of the EASM and East Asian winter monsoon intervals. The calcareous zones were also found to have high Zr/Rb ratio. These indications of shifts from a strong EASM to East Asian winter monsoon dominance correlate well with the cooling transition indicated by deep sea delta O-18 isotopes. This evidence suggests that the EAM was active during the late Miocene and Pliocene and was similar to the Quaternary monsoon. The presence of a strong EAM during the Pliocene Warm Period also raises questions about the hypothesis that past and future warm climate conditions could produce a permanent El Nino-like state.</p