36 research outputs found
Abstract 1603: NKTR-255 engages the IL-15 pathway driving CD8 T cell survival and CD8 memory T cell proliferation
No full textAbstract
Background: IL-15, an immunostimulatory cytokine, plays an important role in both the innate and adaptive immune system. Notably, this pleiotropic cytokine is a key regulator of homeostasis and survival of CD8 and CD8 memory T cells. Targeting the IL-15 pathway has therefore become a promising therapeutic approach in oncology through the induction of long-term T cell activation and durable memory responses. NKTR-255 is a polymer-engineered IL-15 that as a single-agent reduces tumor burden in various tumor models. Here, we show that the anti-tumor effects of NKTR-255 can be attributed to its modulation of survival and proliferation of CD8 and memory CD8 T cells.
Methods: Immunophenotyping of CD8 T cell subpopulations was performed in naïve and tumor-bearing Balb/c mice treated with NKTR-255. Cell surface staining of CD3, CD8, CD44, CD62L and Sca-1 was conducted to identify effector (Tem), central (Tcm) and stem (Tscm) memory T cells. Intracellular staining of Ki67 and Bcl-2 were also analyzed by flow cytometry. Human whole blood and PBMCs were stimulated with IL-15 (0.0001-1000ng/ml) or NKTR-255 (0.001-10,000ng/ml). At various time points pSTAT5 response in CD3, CD4, CD8 and NK (CD56 bright and dim) cells was monitored by flow cytometry.
Results: In naive mice, single dose NKTR-255 (dose range 0.06-1mg/kg) increased the proliferation of Tem, Tcm and Tscm CD8 T cells in a dose-dependent manner. Treatment at 0.3 and 1mg/kg dose levels increased proliferation at least 4 fold across the CD8 memory populations. The abundance of CD8 and CD8 memory T cells was still apparent 6 days post-treatment unlike single dose IL-15 which was ineffective. In a CT-26 lung metastasis model, NKTR-255 reduced the number of lung nodules in a dose-dependent manner. A 0.3mg/kg dose level increased Bcl-2 MFI 1.5 fold in CD8 T cells. Furthermore, administration of NKTR-255 at 0.3, 1 or 3mg/kg significantly increased CD8 proliferation in a dose-dependent manner in blood (1.7, 4.6 and 5.3 fold) and spleen (2.5, 5.7 and 6.9 fold) compared to vehicle. The enhanced Bcl-2 expression and CD8 proliferation were accompanied by elevated CD8 T cells in blood (1.5, 2.4, and 3.4 fold increase) and spleen (1.3, 1.7 and 2.3 fold increase). Consistent with increased proliferation and increased Bcl-2 levels observed in vivo, both IL-15 and NKTR-255 showed dose-dependent induction of pSTAT5, a modulator of Bcl-2 expression, in CD4 and CD8 T cells from human whole blood and PBMCs.
Conclusions: NKTR-255 effectively engages the IL-15 pathway as evidenced by its strong induction of CD8 and memory CD8 T cell proliferation and promotion of survival. Combined with sustained activity and potency in human blood and PBMCs, our results support NKTR-255 as a novel tumor immunotherapeutic with great potential.
Citation Format: Peiwen Kuo, Mekhala Maiti, Phi Quach, Murali Addepalli, Arunasree Lanka, Poornachandra Mathamsetti, Christie Fanton, Ping Zhang, Peter Kirk, Takahiro Miyazaki, Jonathan Zalevsky. NKTR-255 engages the IL-15 pathway driving CD8 T cell survival and CD8 memory T cell proliferation [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 1603. doi:10.1158/1538-7445.AM2017-1603</jats:p
Industrial applications of X-Ray Photoelectron Spectroscopy (XPS) in India
No full textThis review paper summarizes the industrial applications of XPS in India from open literature. Many industrial research and development centers in India, except for a few, do not have in-house XPS systems, and leverage either the instruments available at many government laboratories or universities across various locations in India, or their in-house instruments in other parts of the world for their research activities. While XPS is being used for a wide range of applications, based on an exhaustive literature search by the author, an understanding of the scientific basis of the technique as well as related analytical techniques such as X-ray Excited Auger Electron Spectroscopy (XAES) and depth profiling, the instrumentation, the measurement, and interpretation of the results could be improved. This could potentially avoid artifacts as well as misinterpretation of results. This paper also highlights a few key points that must be considered while measuring and interpreting XPS data
Models Predicting Effects of Missense Mutations in Oncogenesis
No full textThe recent avalanche in high-throughput genotyping, next generation sequencing technologies and re-sequencing of cancer genomes has revolutionized the field of cancer genomics. It has generated a humungous amount of mutational data and changed the way the cancer is being studied. Identification and characterization of these mutations and their mutational effect has become one of the major goals of cancer research. We present here a computational geometry approach based on the application of Delaunay tessellation derived four-body statistical potential function where the potentials are directly derived from the high-resolution protein x-ray crystallographic structures utilizing their atomic coordinates. Proteins and their mutants are characterized by potential topological scores and profiles, which measure the relative change in the overall sequence-structure compatibility. Residual scores and profiles are generated which quantify environmental perturbations from wild-type amino acids at every mutational position. We also present here an integrated database of human cancer missense mutations linked to their 3D structures, which has been created with the whole motivation of building a one stop shop of human missense mutations data sets huge and versatile enough to be used for training and testing of machine learning methodologies. With protein data from this database, we illustrate the use of potential topological cores and residual profiles in the prediction of mutational effects on protein structure and function and generating predictive models using machine-learning algorithms. We successfully apply supervised learning to training sets of protein mutants and generate models, which make statistically meaningful predictions of effects of missense mutations on cancer proteins.This work was embargoed by the author and will not be available until May 2015
Knowledge And Attitudes of Anganwadi Workers About Breast Feeding in The Field Practice Area of Tertiary Care Hospital, Hyderabad
No full textBackground: Breast feeding is one of the most important determinants of child survival, birth spacing and prevention of childhood infections. It is important for the Anganwadi workers to have adequate scientific knowledge about breast feeding practices. . Hence this study was conducted to assess the knowledge and attitude of AWW with regards to breast feeding practices.
Methodology: A facility based cross sectional study was conducted covering all 68 ICDS centers. A pretested semi-structured questioner was given to all AWWs. All questions were read out and explained by the author and all queries were clarified.
Results: only 70 % AWW believed that breast feeding should be given on demand and 75 % AWWs believed that bottle is better than katori & spoon for infant feeding. 40% said breastfeeding should be stopped if mother is sick. Most of AWW (98%) believed that almonds and dry fruits increase breast milk secretion.
Conclusion: Present research draws very important conclusions that although knowledge of AWW regarding initiation of breast feeding is high but their knowledge regarding prelecteal feeds, feeding on demand, bottle feeding and breast feeding during sickness needs further improvement
Abstract 5032: Synergy between an engineered cytokine, NKTR-214, and CTLA-4 blockade in murine colon and breast tumor models
No full textAbstract B296: NKTR-214: An immunotherapy with altered selectivity at the IL2 receptor; pharmacokinetics (PK) and pharmacodynamics (PD) in animal models.
No full textAuthor Correction: A detailed map of Higgs boson interactions by the ATLAS experiment ten years after the discovery
No full textIn the version of this article initially published, the ATLAS Collaboration
author names, affiliations and acknowledgements were omitted and
have now been included in the HTML and PDF versions of the article
Author Correction: A detailed map of Higgs boson interactions by the ATLAS experiment ten years after the discovery (Nature, (2022), 607, 7917, (52-59), 10.1038/s41586-022-04893-w)
No full textCorrection to: Nature Published online 4 July 2022 In the version of this article initially published, the ATLAS Collaboration author names, affiliations and acknowledgements were omitted and have now been included in the HTML and PDF versions of the article
Abstract 3265: NKTR-255, a polymer-conjugated IL-15 enhances anti-tumor NK cell responses and synergizes with monoclonal antibodies to provide long-term survival in human lymphoma model
No full textVEGF-C differentially regulates VEGF-A expression in ocular and cancer cells; promotes angiogenesis via RhoA mediated pathway
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