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https://www.readbyqxmd.com/read/28819703/novel-prostate-cancer-immunotherapy-with-a-dna-encoded-anti-prostate-specific-membrane-antigen-monoclonal-antibody
#1
Kar Muthumani, Liron Marnin, Sagar B Kudchodkar, Alfredo Perales-Puchalt, Hyeree Choi, Sangya Agarwal, Veronica L Scott, Emma L Reuschel, Faraz I Zaidi, Elizabeth K Duperret, Megan C Wise, Kimberly A Kraynyak, Kenneth E Ugen, Niranjan Y Sardesai, J Joseph Kim, David B Weiner
Prostate-specific membrane antigen (PSMA) is expressed at high levels on malignant prostate cells and is likely an important therapeutic target for the treatment of prostate carcinoma. Current immunotherapy approaches to target PSMA include peptide, cell, vector or DNA-based vaccines as well as passive administration of PSMA-specific monoclonal antibodies (mAb). Conventional mAb immunotherapy has numerous logistical and practical limitations, including high production costs and a requirement for frequent dosing due to short mAb serum half-life...
August 17, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/28816699/ceruminous-adenoid-cystic-carcinoma-of-external-auditory-canal
#2
Andrew E Ebelhar, Dava S West, Rony K Aouad
An adenoid cystic carcinoma (AdCC) of the ceruminous glands is very rare; its diagnosis is most often challenging, and simple biopsies may be misleading. Our paper describes a case of a circumferential mass of the left ear canal that was initially reported as a basal cell carcinoma on biopsies in the clinic and on frozen sections intraoperatively. The final pathology was an AdCC of the ceruminous glands of the external auditory canal. Our case reflects the difficulty in the diagnosis of an AdCC of the ceruminous gland and the importance of keeping broad differential diagnoses in mind when counseling patients with masses in the ear canals until final pathology is obtained...
August 2017: Journal of International Advanced Otology
https://www.readbyqxmd.com/read/28814388/the-impact-of-poxvirus-vector-priming-protein-co-administration-and-vaccine-intervals-on-hiv-gp120-vaccine-elicited-antibody-magnitude-and-function-in-infant-macaques
#3
Bonnie Phillips, Genevieve G Fouda, Josh Eudailey, Justin Pollara, Alan D Curtis, Erika Kunz, Maria Dennis, Xiaoying Shen, Camden Bay, Michael Hudgens, David Pickup, S Munir Alam, Amir Ardeshir, Pamela A Kozlowski, Koen K A Van Rompay, Guido Ferrari, M Anthony Moody, Sallie Permar, Kristina De Paris
Despite success in reducing vertical HIV transmission by maternal antiretroviral therapy, several obstacles limit its efficacy during breastfeeding, and breast-milk transmission is now the dominant mode of mother-to-child transmission (MTCT) of HIV in infants. Thus, a pediatric vaccine is needed to eradicate oral HIV infections in newborns and infants. Utilizing the infant rhesus macaque model, we compared 3 different vaccine regimens: (i) HIV Env protein only; (ii) a poxvirus vector (MVA)-HIV Env prime/HIV Env protein boost, and (iii) co-administration of HIV Env protein and MVA-HIV Env at all time points...
August 16, 2017: Clinical and Vaccine Immunology: CVI
https://www.readbyqxmd.com/read/28811973/nk-cell-dysfunction-in-chronic-lymphocytic-leukemia-is-associated-with-loss-of-the-mature-cells-expressing-inhibitory-killer-cell-ig-like-receptors
#4
Alexander W MacFarlane, Mowafaq Jillab, Mitchell R Smith, R Katherine Alpaugh, Marion E Cole, Samuel Litwin, Michael M Millenson, Tahseen Al-Saleem, Adam D Cohen, Kerry S Campbell
A prospective analysis of natural killer (NK) cell phenotype and function was performed on fresh peripheral blood samples from untreated patients with B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Compared to healthy controls, CD56(dim) NK cells in CLL patients displayed reduced expression of the NKG2D activating receptor and increased CD27 expression, which indicates declines in mature cells. In addition, NK cells from CLL patients showed reduced degranulation responses toward transformed B cells alone or with rituximab and were more sensitive to activation-induced cell death...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28802255/simultaneous-targeting-of-two-distinct-epitopes-on-met-effectively-inhibits-met-and-hgf-driven-tumor-growth-by-multiple-mechanisms
#5
Michael M Grandal, Serhiy Havrylov, Thomas Tuxen Poulsen, Klaus Koefoed, Anna Dahlman, Gunther R Galler, Paolo Conrotto, Sara Collins, Karsten W Eriksen, Dafna Kaufman, George F Vande Woude, Helle J Jacobsen, Ivan D Horak, Michael Kragh, Johan Lantto, Thomas Bouquin, Morag Park, Mikkel Wandahl Pedersen
Increased MET activity is linked with poor prognosis and outcome in several human cancers currently lacking targeted therapies. Here we report on the characterization of Sym015, an antibody mixture composed of two humanized IgG1 antibodies against non-overlapping epitopes of MET. Sym015 was selected by high-throughput screening searching for antibody mixtures with superior growth inhibitory activity against MET-dependent cell lines. Synergistic inhibitory activity of the antibodies comprising Sym015 was observed in several cancer cell lines harboring amplified MET locus and was confirmed in vivo Sym015 was found to exert its activity via multiple mechanisms...
August 11, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28794022/potent-in-vivo-nk-cell-mediated-elimination-of-hiv-1-infected-cells-mobilized-by-a-gp120-bispecific-and-hexavalent-broadly-neutralizing-fusion-protein
#6
Ariola Bardhi, Yanling Wu, Weizao Chen, Zhongyu Zhu, Jian Hua Zheng, Hing Wong, Emily Jeng, Jennifer Jones, Christina Ochsenbauer, John C Kappes, Dimiter S Dimitrov, Tianlei Ying, Harris Goldstein
Antibodies bound to HIV-1 envelope protein expressed by infected cells mobilize antibody dependent cellular cytotoxicity (ADCC) to eliminate the HIV-1-infected cells and thereby suppress HIV-1 infection and delay disease progression. Studies treating HIV-1-infected individuals with latency reactivation agents to reduce their latent HIV-1 reservoirs indicated that their HIV-1-specific immune responses were insufficient to effectively eliminate the reactivated latent HIV-1-infected T cells. Mobilization of ADCC may facilitate elimination of reactivated latent HIV-1-infected cells to deplete the HIV-1 reservoir and contribute to functional HIV-1 cure...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28790065/gsk-3-inhibition-drives-maturation-of-nk-cells-and-enhances-their-antitumor-activity
#7
Frank Cichocki, Bahram Valamehr, Ryan Bjordahl, Bin Zhang, Betsy Rezner, Paul Rogers, Svetlana Gaidarova, Stacey K Moreno, Katie Tuininga, Phillip Dougherty, Valarie McCullar, Peter Howard, Dhifaf Sarhan, Emily Taras, Heinrich Schlums, Stewart E Abbot, Daniel Shoemaker, Yenan T Bryceson, Bruce R Blazar, Scott Wolchko, Sarah Cooley, Jeffrey S Miller
Maturation of human natural killer cells (NK cells) as defined by accumulation of cell surface expression of CD57 is associated with increased cytotoxic character and TNF and IFN-γ production upon target cell recognition. Notably, multiple studies point to a unique role for CD57(+) NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacological inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL-15 greatly enhances CD57 upregulation and late-stage maturation...
August 8, 2017: Cancer Research
https://www.readbyqxmd.com/read/28778085/investigation-of-factors-affecting-the-efficacy-of-3c23k-a-human-monoclonal-antibody-targeting-misiir
#8
Sarah E Gill, Qing Zhang, Gary L Keeney, William A Cliby, S John Weroha
MISIIR is a potential target for ovarian cancer (OC) therapy due to its tissue-specific pattern of expression. 3C23K is a novel therapeutic monoclonal anti-MISIIR antibody designed to recruit effector cells and promote cell death through ADCC (antibody dependent cell-mediated cytotoxicity). Our objective was to determine the tolerability and efficacy of 3C23K in OC patient-derived xenografts (PDX) and to identify factors affecting efficacy. Quantitative RT-PCR, immunohistochemistry (IHC), and flow cytometry were used to categorize MISIIR expression in established PDX models derived from primary OC patients...
July 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28776433/cross-reactive-influenza-specific-antibody-dependent-cellular-cytotoxicity-mediating-antibodies-in-hiv-infected-indian-individuals
#9
Sanketkumar Nehul, Archana Kulkarni, Shailesh Pawar, Sheela Godbole, Manisha Ghate, Madhuri Thakar
BACKGROUND: The influenza-specific antibodies mediating antibody-dependent cellular cytotoxicity (ADCC) may be important in protection against influenza. However, it is not known whether immunocompromised individuals such as HIV-infected persons who have never been vaccinated with influenza vaccine have such a response. METHODS: The anti-influenza ADCC responses were investigated in plasma samples from 50 HIV positive persons [25 long-term nonprogressors (LTNPs) and 25 progressors] and from 20 HIV-uninfected healthy individuals...
August 4, 2017: Infectious Diseases
https://www.readbyqxmd.com/read/28771513/a-modified-vaccinia-ankara-vaccine-vector-expressing-a-mosaic-h5-hemagglutinin-reduces-viral-shedding-in-rhesus-macaques
#10
Nicholas W Florek, Attapon Kamlangdee, James P Mutschler, Brock Kingstad-Bakke, Nancy Schultz-Darken, Karl W Broman, Jorge E Osorio, Thomas C Friedrich
The rapid antigenic evolution of influenza viruses requires frequent vaccine reformulations. Due to the economic burden of continuous vaccine reformulation and the threat of new pandemics, there is intense interest in developing vaccines capable of eliciting broadly cross-reactive immunity to influenza viruses. We recently constructed a "mosaic" hemagglutinin (HA) based on subtype 5 HA (H5) and designed to stimulate cellular and humoral immunity to multiple influenza virus subtypes. Modified vaccinia Ankara (MVA) expressing this H5 mosaic (MVA-H5M) protected mice against multiple homosubtypic H5N1 strains and a heterosubtypic H1N1 virus...
2017: PloS One
https://www.readbyqxmd.com/read/28762488/a-real-time-cytotoxicity-assay-as-an-alternative-to-the-standard-chromium-51-release-assay-for-measurement-of-human-nk-and-t-cell-cytotoxic-activity
#11
Julien Fassy, Kyriaki Tsalkitzi, Maria Goncalves-Maia, Véronique M Braud
This unit describes the monitoring and quantification of cellular cytotoxicity using a non-radioactive and real-time cytotoxic assay. The extent of target-cell lysis is monitored over time by imaging and quantifying live fluorescent target cells using a cell-imaging multimode reader. This assay is performed in a 96 well plate in optimized culture conditions at 37°C in the presence of 5% CO2 . The basic protocol describes natural killer cell-mediated cytotoxic assay that can be adapted to include antibodies blocking inhibitory NK receptors or triggering antibody-dependent cell-mediated cytotoxicity (ADCC)...
August 1, 2017: Current Protocols in Immunology
https://www.readbyqxmd.com/read/28753113/a-potential-therapy-for-chordoma-via-antibody-dependent-cell-mediated-cytotoxicity-employing-nk-or-high-affinity-nk-cells-in-combination-with-cetuximab
#12
Rika Fujii, Jeffrey Schlom, James W Hodge
OBJECTIVE Chordoma is a rare bone tumor derived from the notochord and is resistant to conventional therapies such as chemotherapy, radiotherapy, and targeting therapeutics. Expression of epidermal growth factor receptor (EGFR) in a large proportion of chordoma specimens indicates a potential target for therapeutic intervention. In this study the authors investigated the potential role of the anti-EGFR antibody cetuximab in immunotherapy for chordoma. METHODS Since cetuximab is a monoclonal antibody of the IgG1 isotype, it has the potential to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) employing natural killer (NK) cells as effectors...
July 28, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/28739115/a-recombinant-protein-of-salmonella-typhi-induces-humoral-and-cell-mediated-immune-responses-including-memory-responses
#13
Sayan Das, Rimi Chowdhury, Shubhamoy Ghosh, Santasabuj Das
Gram negative enteric bacteria, Salmonella enterica serovar Typhi (S. Typhi), the etiological agent of typhoid fever is a major public health problem in developing countries. While a permanent solution to the problem would require improved sanitation, food and water hygiene, controlling the infection by vaccination is urgently required due to the emergence of multidrug resistant strains in multiple countries. The currently licensed vaccines are moderately efficacious with limited applicability, and no recommended vaccines exist for younger children...
July 21, 2017: Vaccine
https://www.readbyqxmd.com/read/28735814/tyrosine-kinase-inhibitors-as-modulators-of-trastuzumab-mediated-antibody-dependent-cell-mediated-cytotoxicity-in-breast-cancer-cell-lines
#14
Denis M Collins, Kathy Gately, Clare Hughes, Connla Edwards, Anthony Davies, Stephen F Madden, Kenneth J O'Byrne, Norma O'Donovan, John Crown
BACKGROUND: Trastuzumab is an anti-HER2 monoclonal antibody (mAb) therapy capable of antibody-dependent cell-mediated cytotoxicity (ADCC) and used in the treatment of HER2+ breast cancer. Through interactions with FcƴR+ immune cell subsets, trastuzumab functions as a passive immunotherapy. The EGFR/HER2-targeting tyrosine kinase inhibitor (TKI) lapatinib and the next generation TKIs afatinib and neratinib, can alter HER2 levels, potentially modulating the ADCC response to trastuzumab...
July 15, 2017: Cellular Immunology
https://www.readbyqxmd.com/read/28727817/immunogenicity-of-a-novel-clade-b-hiv-1-vaccine-combination-results-of-phase-1-randomized-placebo-controlled-trial-of-an-hiv-1-gm-csf-expressing-dna-prime-with-a-modified-vaccinia-ankara-vaccine-boost-in-healthy-hiv-1-uninfected-adults
#15
Susan P Buchbinder, Nicole A Grunenberg, Brittany J Sanchez, Kelly E Seaton, Guido Ferrari, M Anthony Moody, Nicole Frahm, David C Montefiori, Christine M Hay, Paul A Goepfert, Lindsey R Baden, Harriet L Robinson, Xuesong Yu, Peter B Gilbert, M Juliana McElrath, Yunda Huang, Georgia D Tomaras
BACKGROUND: A phase 1 trial of a clade B HIV vaccine in HIV-uninfected adults evaluated the safety and immunogenicity of a DNA prime co-expressing GM-CSF (Dg) followed by different numbers and intervals of modified vaccinia Ankara Boosts (M). Both vaccines produce virus-like particles presenting membrane-bound Env. METHODS: Four US sites randomized 48 participants to receiving 1/10th the DNA dose as DgDgMMM given at 0, 2, 4, 6 and 8 months, or full dose DgDgM_M or DgDgMM_M regimens, given at 0, 2, 4, and 8 months, and 0, 2, 4, 6, and 10 months, respectively...
2017: PloS One
https://www.readbyqxmd.com/read/28723675/tumor-antigen-ca125-suppresses-antibody-dependent-cellular-cytotoxicity-adcc-via-direct-antibody-binding-and-suppressed-fc-%C3%AE-receptor-engagement
#16
James Bradford Kline, Rina P Kennedy, Earl Albone, Qimin Chao, Shawn Fernando, Jennifer M McDonough, Katherine Rybinski, Wenquan Wang, Elizabeth B Somers, Charles Schweizer, Luigi Grasso, Nicholas C Nicolaides
Cancers employ a number of mechanisms to evade host immune responses. Here we report the effects of tumor-shed antigen CA125/MUC16 on suppressing IgG1-mediated antibody-dependent cellular cytotoxicity (ADCC). This evidence stems from prespecified subgroup analysis of a Phase 3 clinical trial testing farletuzumab, a monoclonal antibody to folate receptor alpha, plus standard-of-care carboplatin-taxane chemotherapy in patients with recurrent platinum-sensitive ovarian cancer. Patients with low serum CA125 levels treated with farletuzumab demonstrated improvements in progression free survival (HR 0...
July 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28710915/potent-therapeutic-activity-against-peritoneal-dissemination-and-malignant-ascites-by-the-novel-anti-folate-receptor-alpha-antibody-khk2805
#17
Munetoshi Ando, Keiko Nagata, Kaito Nihira, Yui Suzuki, Yutaka Kanda, Maiko Adachi, Tsuguo Kubota, Naoya Kameyama, Mariko Nakano, Hiroshi Ando, Kazuya Yamano, Toshihiko Ishii, Ryuichiro Nakai, Kazuyasu Nakamura
Many ovarian cancer patients often show peritoneal metastasis with malignant ascites. However, unmet medical needs remain regarding controlling these symptoms after tumors become resistant to chemotherapies. We developed KHK2805, a novel anti-folate receptor α (FOLR1) humanized antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The primary aim of the present study was to evaluate whether the anti-tumor activity of KHK2805 was sufficient for therapeutic application against peritoneal dissemination and malignant ascites of platinum-resistant ovarian cancer in preclinical models...
July 11, 2017: Translational Oncology
https://www.readbyqxmd.com/read/28705408/superior-in-vitro-and-in-vivo-activity-of-trastuzumab-emtansine-t-dm1-in-comparison-to-trastuzumab-pertuzumab-and-their-combination-in-epithelial-ovarian-carcinoma-with-high-her2-neu-expression
#18
Gulden Menderes, Elena Bonazzoli, Stefania Bellone, Gary Altwerger, Jonathan D Black, Katherine Dugan, Francesca Pettinella, Alice Masserdotti, Francesco Riccio, Anna Bianchi, Luca Zammataro, Christopher de Haydu, Natalia Buza, Pei Hui, Serena Wong, Gloria S Huang, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
BACKGROUND: Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. The objective of this study was to compare the anti-tumor activity of HER2/neu-targeting monoclonal antibodies, trastuzumab (T), pertuzumab (P), combination of trastuzumab and pertuzumab (T+P) and trastuzumab-emtansine (T-DM1) in EOC with high HER2/neu expression. METHODS: Primary EOC cell lines were established and cell blocks were analyzed for HER2/neu expression. Cytostatic, apoptotic and antibody-dependent cell-mediated cytotoxicity (ADCC) activities of T, P, T+P and T-DM1 were evaluated in vitro...
July 10, 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28701403/monoclonal-antibodies-derived-from-humans-vaccinated-with-the-rv144-hiv-vaccine-containing-the-hvem-binding-domain-of-herpes-simplex-virus-hsv-glycoprotein-d-neutralize-hsv-infection-mediate-adcc-and-protect-mice-from-ocular-challenge-with-hsv-1
#19
Kening Wang, Georgia D Tomaras, Sinthujan Jegaskanda, M Anthony Moody, Hua-Xin Liao, Kyle Goodman, Phillip W Berman, Supachai Rerks-Ngarm, Punnee Pitisuttithum, Sorachai Nitayapan, Jaranit Kaewkungwal, Barton F Haynes, Jeffrey I Cohen
The RV144 HIV vaccine trial included a recombinant HIV glycoprotein 120 (gp120) construct fused to a small portion of herpes simplex virus (HSV-1) glycoprotein D (gD), such that the first 40 amino acids of gp120 were replaced by the signal sequence and the first 27 amino acids of the mature form of gD. This region of gD contains most of the binding site for HVEM, an HSV receptor important for virus infection of epithelial cells and lymphocytes. RV144 induced antibodies to HIV that were partially protective against infection as well as antibodies to HSV...
July 12, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28701402/increased-durable-b-cell-and-adcc-responses-associated-with-t-helper-responses-to-hiv-1-envelope-in-macaques-vaccinated-with-gp140-occluded-at-the-cd4-receptor-binding-site
#20
Willy M J M Bogers, Susan W Barnett, Herman Oostermeijer, Ivonne G Nieuwenhuis, Niels Beenhakker, Daniella Mortier, Petra Mooij, Gerrit Koopman, Edmund Remarque, Gregoire Martin, Rachel Pei-Jen Lai, Antu K Dey, Yide Sun, Brian Burke, Guido Ferrari, David Montefiori, Loic Martin, David Davis, Indresh Srivastava, Jonathan L Heeney
Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens for more long lived, efficacious HIV-1 vaccine induced B-cell responses. HIV-1 Env gp140 (native or un-cleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells may result in anergic effects on T-cell recruitment and consequently a lack of strong robust and durable B-memory responses. To test this hypothesis we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3kD CD4 miniprotein mimetic serving to block ligation of gp140 on CD4+T-cells while preserving CD4 inducible (CDi) neutralizing and epitopes targeted by antibody dependent cellular cytotoxic (ADCC) effector responses...
July 12, 2017: Journal of Virology
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