102 research outputs found
Abstract A41: Combination immunotherapy leads to decreased tumor growth
No full textAbstract
Introduction/Background: Talimogene Laherparepvec (T-Vec) is the first oncolytic virus to be FDA approved for the treatment of cancer. T-Vec, a modified Herpes Simplex Type I virus (HSV I), has two mechanisms of action: direct cell lysis and immune activation. Combination immunotherapy using T-Vec and check-point blockade has shown promise in clinical trials.1 In preliminary work, our lab has shown that T-Vec causes up-regulation of programmed cell death protein 1 (PD-1) on infiltrating T cells in mice, suggesting potential synergy of T-Vec and anti-PD1 (α-PD1). The purpose of our study is to evaluate the effectiveness of combination immunotherapy to treat melanoma tumors in a transgenic BRAF melanoma model and study the immune microenvironment of these tumors post treatment.
Materials and Methods: In a temporally and spatially regulated murine model of BRAFCA PTEN-/- spontaneous melanoma2, tumors are induced on the shaved right flank of mice. When tumors reach ≥5mm in diameter, mice are randomized into 6 treatment groups comparing combinations of BRAF inhibition (BRAFi) or control chow, intraperitoneal injections of α-PD1 or control (2A3), and intratumoral injections of T-Vec or control (PBS) by intratumoral injection.
Treatment Groups:
1: Control + 2A3 + PBS
2: BRAFi + 2A3 + PBS
3: BRAFi + α-PD1 + PBS
4: BRAFi + 2A3 + T-Vec
5: BRAFi + α-PD1 + T-Vec
6: Control + α-PD1 + T-Vec
Tumor growth is measured biweekly until end of study. Flow cytometry is performed on tumor, lymph node, and spleen to assess immune microenvironment. Multiplex immunohistochemistry will also be performed and analyzed with Mantra, using 6 immune biomarkers.
Results: Mean tumor volume and survival was plotted to compare groups. Mice treated with combination T-Vec + BRAFi with or without α-PD1 have decreased tumor growth and longer survival compared to mice treated with control or single drug arms. Flow cytometry shows an increase in percent CD3+ cells in tumors of mice treated with combination α-PD1 + T-Vec compared to the control and single drug arms. Further analysis revealed very few CD45+ cells in tumors of the control group whilst mice receiving combination immunotherapy without BRAFi have higher CD45+ cells in tumor. Percent CD8+/CD3+ cells in tumors treated with immunotherapy appears to be increased compared to the control and BRAFi only group. Additionally, percent of CD4+/FOXP3+ cells in tumors appears to be decreased in groups receiving T-Vec while no change in CD4+/FOXP3+ populations was observed in draining lymph node or spleen.
Conclusions: Initial findings show that combination therapy of BRAFi + α-PD1 + T-Vec is more effective than any single treatment. Combination immunotherapy increases infiltration of T cells into tumor. Furthermore, oncolytic virus appears to decrease CD4+/FOXP3+ (regulatory T cells) infiltrating tumor. This study is ongoing and further analysis will continue as we further evaluate the immune microenvironment using flow cytometry and immunohistochemistry.
Acknowledgements: The study was funded by the Melanoma Research Alliance and Amgen (Amgen-CUMC-MRA Established Investigator Academic-Industry Partnership Award).
References:
1. Andtbacka, R.H.I., et al. OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. ASCO Meeting Abstracts 31, LBA9008 (2013).
2. Dankort, D., et al. Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. Nature genetics 41, 544-552 (2009).
Citation Format: Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Sato, Yingzhi Qian, James Zhang, Yan Lu, Yvonne Saenger. Combination immunotherapy leads to decreased tumor growth. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A41.</jats:p
Nematode infections of kiwi (Apteryx spp.) : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Veterinary Science at Massey University, Palmerston North, New Zealand
No full textCopyright is owned by the Author of the thesis. Permission is given for a copy to be downloaded by an individual for the purpose of research and private study only. The thesis may not be reproduced elsewhere without the permission of the Author.Overall, little is known about the nematodes of kiwi (Apteryx spp.) and there has, thus far, been little indication that such infections are associated with significant clinical disease in these species. However, over the past 15 to 20 years there has been increasing recognition of cases of nematode larva migrans identified in kiwi at necropsy, caused by the aberrant migration of nematode larvae within visceral organs and brain. The initial study of this research re-examines archived cases of larva migrans through DNA extraction and PCR using formalin-fixed, paraffin-embedded tissue sections. Sequencing and BLAST analysis of positive results showed 100% alignment to database sequences from Toxocara cati, a nematode parasite whose definitive host is the domestic cat, indicating an infection acquired from an invasive mammalian species. Following the success of this methodology, similar techniques were applied to archived biopsies from an outbreak of cutaneous nematodiasis in a geographically isolated population of juvenile rowi kiwi (Apteryx rowi). The resultant sequences aligned among members of the capillarid genus Eucoleus although without an exact match present in the database, and so the precise, species-level identification and original source of this unusual presentation of cutaneous capillariasis remains unknown. Concurrent with these investigations into aberrant nematode infections, an opportunistic, prospective survey that included 50 kiwi presenting for necropsy examination was performed, with the objective of examining as far as practicable the prevalence, diversity, and potential pathogenicity of gastrointestinal nematodes, including any potential association with aberrant migratory lesions. The results confirmed that gastrointestinal nematodiasis was common, with 94% of the kiwi examined infected to some degree, and at least five morphologically distinct nematode types were found. Species-level identification of the nematodes was not reached based on limited morphological and molecular evaluations. However, while such gastrointestinal nematode infections appeared on the whole to be well-tolerated by the kiwi hosts, occasional cases of significant ventriculitis were identified in association with gizzard infections, particularly in juvenile, captive-bred kiwi. Furthermore, histological lesions consistent with nematode larva migrans were identified in around 43% of the survey kiwi in which visceral sections were also examined, indicating that this disease may be routinely under-diagnosed
Abstract 1671: Characterization of the immune landscape in stage II-III melanoma using qIF
No full textAbstract
Background: The tumor microenvironment plays a crucial role in cancer progression, often supporting immune evasion. This is of particular importance in melanoma, where immune checkpoint therapies have resulted in significant clinical benefit, yet only in a subset of melanoma patients respond. Precise biomarkers are urgently needed to characterize the tumor immune micro-environment, both for prognostication and to predict the benefit of immuno-therapeutic intervention. HLA-DR on tumor cells and Ki67 on cytotoxic (CD8+) T cells have been proposed as biomarkers of anti-PD1 activity. Quantitative immunofluorescence (qIF) allows for automated quantitation of phenotypes and spatial distributions of immune cell populations within formalin fixed paraffin embedded (FFPE) tissues.
Methods: To characterize the tumor immune microenvironment, we screened databases at the Herbert Irving Cancer Center (HICC) at Columbia University for early stage melanoma patients with documented clinical follow up. We identified a preliminary population of 40 stage II-III melanoma patients diagnosed between 2000 and 2012. Clinical follow up was available on 21 patients, 12 of whom were alive with no evidence of recurrence, 1 who died of another malignancy, and 8 who died of melanoma. 19 patients had more than 24 months of survival information available but no detailed clinical information. 5µm slides from either primary biopsy or subsequent wide local excision procedure were stained using qIF for DAPI, CD3, CD8, CD68, SOX10, HLA-DR and Ki67. Cell phenotypes within representative fields selected by a trained dermatopathologist (BH), were visualized using multispectral imaging, and analysis of spatial distribution of cells were analyzed using inForm image analysis software (Perkin Elmer), and Spotfire software (TIBCO).
Results: We were able to quantify and identify coordinates for multiple immune cell subsets in melanoma tissues. In 21 patients with clinical follow up, we found that higher densities of CD3+CD8+ T cells in tumor and stroma trended towards correlation with non-recurrence. In addition, CD68+HLA-DR- predicts poor prognosis (p&lt;0.05), whether in tumor or stroma. Assessment of spatial distribution across all 40 tumors demonstrated that CD3+CD8+ cells are closer to CD68+ cells and Sox10+ tumor cells when they express HLA-DR (p&lt;0.001). Conversely, CD3+CD8+ cells are significantly farther from tumor cells when they express Ki-67, (p&lt;0.001). Among patients with clinical follow up, CD3+CD8+ cells were closer to CD68+HLA-DR- cells in recurrent patients (p &lt; 0.05).
Conclusion: Using qIF imaging and analysis we find that density and spatial relationships of immune cell subsets correlates with recurrence status. qIF may offer the potential for the development of prognostic biomarkers in stage II/III melanoma.
Citation Format: Robyn Gartrell, Douglas Marks, Edward C. Stack, Yan Lu, Thomas D. Hart, Camille Gerard, Camden Esancy, Dan Tong Jia, Paul Armenta, Daisuke Izaki, Danielle Davari, Ashley White-Stern, Zoe Blake, Yichun Fu, Basil Horst, Yvonne Saenger. Characterization of the immune landscape in stage II-III melanoma using qIF [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 1671. doi:10.1158/1538-7445.AM2017-1671</jats:p
How early childhood teachers build positive relationships with their students to support learning
No full textThe purpose of this study was to better understand how early childhood teachers could build positive relationships with their students to support learning. The study explores why teacher-student relationships are important, the attributes that describe positive teacher-student relationships, how these relationships are connected to academic learning, and some approaches used to intentionally develop positive teacher-student relationships in early childhood classrooms. A key influence was the work of Pianta, La Paro, and Hamre (2008) and their development of the Classroom Assessment Scoring System (CLASS), an observational framework measuring classroom interactions associated with high quality instruction. A strategy called \u27contact talks\u27, developed by Dan Gartrell, was introduced to teachers as one way of building relationships. The author concluded positive teacher-student relationships are a critical element of instructional support and best practice and therefore must be intentionally addressed in teacher reflection, education, and professional development
The Cauldron 2007-2008
No full textContents : Centipede / by Sonnet Claire Eder
-- Push / by Heather Weatherly
-- Crazy Amy / by Amy Jo Klamm
-- Smelly Kid / by Sally Warner
-- Braiding Erica’s Hair / by Robyn McBride
-- Thirsty / by Peter Hopkins
-- When I Was Bad / by Amy Jo Klamm
-- Pickings From Slim / by Brian G. Barkley
-- Autopsy/Birth / by Louis Jeannot
-- The rusty nails that lay on the ground / by Maghan Jackson
-- Empty Fulfillment / by Nora Seilheimer
-- Emerge / by Elayna Snyder
-- The Pick-up / by Peter Hopkins
-- Bad Beat / by Jimmy Kelly
-- Yoga Class / by Sara Goldstein
-- A Rebuttal to Keats / by Rachel Jeffery
-- Lorenzo / by Bryn Davis
-- Streetz / by Brandon Scarber
-- Attack of the Spider-Woman from Mars / by Joseph Schafer
-- Expectations / by Kira Dow
-- An Affair with Light / by Kelly Hurd
-- Where the Mouth Begins / by Colleen Bednar
-- October 7th / by Adam Marshall
--Preparation / by Brandon Scarber
-- For the Haunted Happiness of Useless Time / by Danielle Badra
-- Breaks in Skin / by Danielle Badra
-- Iron / by Jessica Bard
-- Tomatoes / by Jessica Maas
-- Japanese Christmas / by Eric Michaelsen
-- Smashed Dylan / by Seuss-Brakeman
-- Embracing Diversity / by “Reba Rebecca”
-- Mirror Image of Coffee / by Rebecca Aulph
-- Baucis and Philemon / by Sarah Shuster-Tucker
-- Manos / by Sally Warner
-- Fire and Water / by Megan O’Neill
-- This is the Wedding / by Emma Perry
-- Fleetwood Diner / by Jenneva Schultz
-- Waiting on the Moon / by Nora Seilheimer
-- CS Lewis / by Jessica Bard
-- Las Peregrinas / by Julia Dean
-- Too Close to the Sun / by Alanna Muto
-- Negative Space/ by Kelsay Myers
-- Living Room from Niles Senes / by Dylan Seuss-Brakeman
-- The Well / by Maghan Jackson
-- Buttons and Zippers / by Robyn McBride
-- Quilt / by Julia Gartrell
-- Fish and Chips / by Jeanette Lee
-- China Shop / by Colleen Bednar
-- Thinly Drawn / by Natalia Holtzman
-- It Looks Like Rain / by Jared Devitt
-- My Brother’s Wake / by Melissa Burnette
-- Antraq / by Jillian Regal
-- Casita / by Jessica Bard
-- Scarlet Fever / by Martin Goffeney
-- Stone Umbrella / by Ryan Booms
-- Dead Things / by Colleen Bednar
-- Obesity / by Michelle Lamont
-- Cancer Chronicles / by Sara Goldstein
-- A New Way to Kiss the Blues Goodbye / by Louis Jeannot
-- Time after Time / by Heather Weatherly.
Student Art Credits : Liz Wilson, Dylan Seuss-Brakeman
Abstract B005: Linking transcriptomic and imaging features of the melanoma tumor microenvironment
No full textAuthor Correction: Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma
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