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Gerard Zurawski, Xiaoying Shen, Sandra Zurawski, Georgia D Tomaras, David C Montefiori, Mario Roederer, Guido Ferrari, Christine Lacabaratz, Peter Klucar, Zhiqing Wang, Kathryn E Foulds, Shing-Fen Kao, Xuesong Yu, Alicia Sato, Nicole L Yates, Celia LaBranche, Sherry Stanfield-Oakley, Karen Kibler, Bertram Jacobs, Andres Salazar, Steve Self, Jimmy Fulp, Raphael Gottardo, Lindsey Galmin, Deborah Weiss, Anthony Cristillo, Giuseppe Pantaleo, Yves Levy
We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in Rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly ICLC adjuvant either alone or co-administered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to P =0...
February 15, 2017: Journal of Virology
Ian F Pollack, Regina I Jakacki, Lisa H Butterfield, Ronald L Hamilton, Ashok Panigrahy, Daniel P Normolle, Angela K Connelly, Sharon Dibridge, Gary Mason, Theresa L Whiteside, Hideho Okada
Recurrent high-grade gliomas (HGGs) of childhood have an exceedingly poor prognosis with current therapies. Accordingly, new treatment approaches are needed. We initiated a pilot trial of vaccinations with peptide epitopes derived from glioma-associated antigens (GAAs) overexpressed in these tumors in HLA-A2+ children with recurrent HGG that had progressed after prior treatments. Peptide epitopes for three GAAs (EphA2, IL13Rα2, survivin), emulsified in Montanide-ISA-51, were administered subcutaneously adjacent to intramuscular injections of poly-ICLC every 3 weeks for 8 courses, followed by booster vaccines every 6 weeks...
December 2016: Journal of Neuro-oncology
Krishnamurthy Konduru, Amy C Shurtleff, Steven B Bradfute, Siham Nakamura, Sina Bavari, Gerardo Kaplan
Ebola virus (EBOV), a member of the Filoviridae that can cause severe hemorrhagic fever in humans and nonhuman primates, poses a significant threat to the public health. Currently, there are no licensed vaccines or therapeutics to prevent and treat EBOV infection. Several vaccines based on the EBOV glycoprotein (GP) are under development, including vectored, virus-like particles, and protein-based subunit vaccines. We previously demonstrated that a subunit vaccine containing the extracellular domain of the Ebola ebolavirus (EBOV) GP fused to the Fc fragment of human IgG1 (EBOVgp-Fc) protected mice against EBOV lethal challenge...
2016: PloS One
Elena Gonzalez-Gugel, Mansi Saxena, Nina Bhardwaj
A recent report from the Center for Disease Control identified melanoma as being among the highest causes of cancer-related mortalities in the USA. While interventions such as checkpoint blockade have made substantial impact in terms of improving response rates and overall survival, a significant number of patients fail to respond to treatment or become resistant to therapy. A better understanding of the tumor microenvironment in these patients becomes imperative for identifying immune suppressive mechanisms that impact the development of effective anti-tumor immune responses...
October 2016: Cancer Immunology, Immunotherapy: CII
Bo Liu, Xia Wang, Tai-Zhong Chen, Guang-Liang Li, Chang-Chun Tan, Yong Chen, Shao-Qiang Duan
OBJECTIVE: To investigate the correlation between activation of toll-like receptors 3 (TLR3) signaling pathway and tumor-associated macrophage and its effect on the tumor growth. METHODS: The mice Lewis lung cancer cell lines 3LL and melanoma B16H10 were used to construct the subcutaneous transplantation tumor models and then they were treated with Poly-ICLC. The curative effect was observed and then the T cell and macrophage phenotypes infiltrated in local tumor were detected by flow cytometry...
May 2016: Asian Pacific Journal of Tropical Medicine
Gerard Zurawski, Sandra Zurawski, Anne-Laure Flamar, Laura Richert, Ralf Wagner, Georgia D Tomaras, David C Montefiori, Mario Roederer, Guido Ferrari, Christine Lacabaratz, Henri Bonnabau, Peter Klucar, Zhiqing Wang, Kathryn E Foulds, Shing-Fen Kao, Nicole L Yates, Celia LaBranche, Bertram L Jacobs, Karen Kibler, Benedikt Asbach, Alexander Kliche, Andres Salazar, Steve Reed, Steve Self, Raphael Gottardo, Lindsey Galmin, Deborah Weiss, Anthony Cristillo, Rodolphe Thiebaut, Giuseppe Pantaleo, Yves Levy
Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses...
2016: PloS One
Ian F Pollack, Regina I Jakacki, Lisa H Butterfield, Ronald L Hamilton, Ashok Panigrahy, Daniel P Normolle, Angela K Connelly, Sharon Dibridge, Gary Mason, Theresa L Whiteside, Hideho Okada
BACKGROUND: Low-grade gliomas (LGGs) are the most common brain tumors of childhood. Although surgical resection is curative for well-circumscribed superficial lesions, tumors that are infiltrative or arise from deep structures are therapeutically challenging, and new treatment approaches are needed. Having identified a panel of glioma-associated antigens (GAAs) overexpressed in these tumors, we initiated a pilot trial of vaccinations with peptides for GAA epitopes in human leukocyte antigen-A2+ children with recurrent LGG that had progressed after at least 2 prior regimens...
August 2016: Neuro-oncology
Mohamed L Salem, Zeinab I Attia, Sohaila M Galal
Given the self nature of cancer, anti-tumor immune response is weak. As such, acute inflammation induced by microbial products can induce signals that result in initiation of an inflammatory cascade that helps activation of immune cells. We aimed to compare the nature and magnitude of acute inflammation induced by toll-like receptor ligands (TLRLs) on the tumor growth and the associated inflammatory immune responses. To induce acute inflammation in tumor-bearing host, CD1 mice were inoculated with intraperitoneal (i...
March 2016: Journal of Advanced Research
Karen A O Martins, Christopher L Cooper, Sabrina M Stronsky, Sarah L W Norris, Steven A Kwilas, Jesse T Steffens, Jacqueline G Benko, Sean A van Tongeren, Sina Bavari
Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP) as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge...
January 2016: EBioMedicine
Si-Yeon Jeong, Raok Jeon, Yoon Kyung Choi, Joo Eun Jung, Anna Liang, Changhong Xing, Xiaoying Wang, Eng H Lo, Yun Seon Song
Emerging experimental evidence suggests that activation of Toll like receptor 3 (TLR3) by its agonist polyinosinic polycytidylic acid (poly-ICLC) protects neurons against cerebral ischemia, but the underlying mechanisms remain largely unknown. In the brain, TLR3 is mostly expressed in glial cells. Therefore, we assess the hypothesis that TLR3 activation in microglia is required for neuroprotection against ischemia. After transient focal cerebral ischemia, microglia/macrophages (MMs) demonstrate a significant reduction in TLR3 and its downstream cytokine Interleukin 6 (IL-6)...
November 25, 2015: Journal of Neurochemistry
Raffaella Gesuete, Sara N Christensen, Frances R Bahjat, Amy E B Packard, Susan L Stevens, Mingyue Liu, Andres M Salazar, Mary P Stenzel-Poore
BACKGROUND AND PURPOSE: Preconditioning with poly-l-lysine and carboxymethylcellulose (ICLC) provides robust neuroprotection from cerebral ischemia in a mouse stroke model. However, the receptor that mediates neuroprotection is unknown. As a synthetic double-stranded RNA, poly-ICLC may bind endosomal Toll-like receptor 3 or one of the cytosolic retinoic acid-inducible gene-I-like receptor family members, retinoic acid-inducible gene-I, or melanoma differentiation-associated protein 5...
January 2016: Stroke; a Journal of Cerebral Circulation
Alfonso R Sánchez-Paulete, Francisco J Cueto, María Martínez-López, Sara Labiano, Aizea Morales-Kastresana, María E Rodríguez-Ruiz, Maria Jure-Kunkel, Arantza Azpilikueta, M Angela Aznar, José I Quetglas, David Sancho, Ignacio Melero
UNLABELLED: Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory mAbs targeting PD-1 or CD137. Using Batf3(-/-) mice, which are defective for cross-presentation of cell-associated antigens, we show that BATF3-dependent dendritic cells (DC) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3(-/-) mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens...
January 2016: Cancer Discovery
Victor Ho, Tong Seng Lim, Justin Lee, Jeffrey Steinberg, Radoslaw Szmyd, Muly Tham, Jadegoud Yaligar, Philipp Kaldis, Jean-Pierre Abastado, Valerie Chew
Hepatocellular carcinoma (HCC) is associated with high mortality and the current therapy for advanced HCC, Sorafenib, offers limited survival benefits. Here we assessed whether combining the TLR3 agonist: lysine-stabilized polyinosinic-polycytidylic-acid (poly-ICLC) with Sorafenib could enhance tumor control in HCC. Combinatorial therapy with poly-ICLC and Sorafenib increased apoptosis and reduced proliferation of HCC cell lines in vitro, in association with impaired phosphorylation of AKT, MEK and ERK. In vivo, the combinatorial treatment enhanced control of tumor growth in two mouse models: one transplanted with Hepa 1-6 cells, and the other with liver tumors induced using the Sleeping beauty transposon...
September 29, 2015: Oncotarget
Edward Sionov, Katrin D Mayer-Barber, Yun C Chang, Keith D Kauffman, Michael A Eckhaus, Andres M Salazar, Daniel L Barber, Kyung J Kwon-Chung
Cryptococcus neoformans is the most common cause of fungal meningoencephalitis in AIDS patients. Depletion of CD4 cells, such as occurs during advanced AIDS, is known to be a critical risk factor for developing cryptococcosis. However, the role of HIV-induced innate inflammation in susceptibility to cryptococcosis has not been evaluated. Thus, we sought to determine the role of Type I IFN induction in host defense against cryptococci by treatment of C. neoformans (H99) infected mice with poly-ICLC (pICLC), a dsRNA virus mimic...
August 2015: PLoS Pathogens
Ruth K Weir, Reihaneh Forghany, Stephen E P Smith, Paul H Patterson, A Kimberly McAllister, Cynthia M Schumann, Melissa D Bauman
Maternal infection during pregnancy increases the risk for neurodevelopmental disorders in offspring. Rodent models have played a critical role in establishing maternal immune activation (MIA) as a causal factor for altered brain and behavioral development in offspring. We recently extended these findings to a species more closely related to humans by demonstrating that rhesus monkeys (Macaca mulatta) prenatally exposed to MIA also develop abnormal behaviors. Here, for the first time, we present initial evidence of underlying brain pathology in this novel nonhuman primate MIA model...
August 2015: Brain, Behavior, and Immunity
Elizabeth Miller, Meredith Spadaccia, Rachel Sabado, Elena Chertova, Julian Bess, Charles Mac Trubey, Rose Marie Holman, Andres Salazar, Jeffrey Lifson, Nina Bhardwaj
Therapeutic interventions for HIV-1 that successfully augment adaptive immunity to promote killing of infected cells may be a requisite component of strategies to reduce latent cellular reservoirs. Adoptive immunotherapies utilizing autologous monocyte-derived dendritic cells (DCs) that have been activated and antigen loaded ex vivo may serve to circumvent defects in DC function that are present during HIV infection in order to enhance adaptive immune responses. Here we detail the clinical preparation of DCs loaded with autologous aldrithiol-2 (AT-2)-inactivated HIV that have been potently activated with the viral mimic, Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (Poly-ICLC)...
January 3, 2015: Vaccine
Hideho Okada, Lisa H Butterfield, Ronald L Hamilton, Aki Hoji, Masashi Sakaki, Brian J Ahn, Gary Kohanbash, Jan Drappatz, Johnathan Engh, Nduka Amankulor, Mark O Lively, Michael D Chan, Andres M Salazar, Edward G Shaw, Douglas M Potter, Frank S Lieberman
PURPOSE: WHO grade 2 low-grade gliomas (LGG) with high risk factors for recurrence are mostly lethal despite current treatments. We conducted a phase I study to evaluate the safety and immunogenicity of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes in HLA-A2(+) adults with high-risk LGGs in the following three cohorts: (i) patients without prior progression, chemotherapy, or radiotherapy (RT); (ii) patients without prior progression or chemotherapy but with prior RT; and (iii) recurrent patients...
January 15, 2015: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Li-Zhen He, Jeffrey Weidlick, Crystal Sisson, Henry C Marsh, Tibor Keler
Previous studies have documented that selective delivery of protein antigens to cells expressing mannose receptor (MR) can lead to enhanced immune responses. We postulated that agents that influenced the MR expression level, and the activation and migration status of MR-expressing antigen presenting cells, would modulate immune responses to MR-targeted vaccines. To address this question, we investigated the effect of clinically used adjuvants in human MR transgenic (hMR-Tg) mice immunized with an MR-targeting cancer vaccine composed of the human anti-MR monoclonal antibody B11 fused with the oncofetal protein, human chorionic gonadotropin beta chain (hCGβ), and referred to as B11-hCGβ...
November 2015: Cellular & Molecular Immunology
Karen A O Martins, Sina Bavari, Andres M Salazar
Pathogen-associated molecular patterns (PAMPs) are stand-alone immunomodulators or 'danger signals,' that are increasingly recognized as critical components of many modern vaccines. Polyinosinic-polycytidylic acid (poly-IC) is a synthetic dsRNA that can activate multiple elements of the host defense in a pattern that parallels that of a viral infection. When properly combined with an antigen, it can be utilized as a PAMP-adjuvant, resulting in modulation and optimization of the antigen-specific immune response...
March 2015: Expert Review of Vaccines
Rachid Ammi, Jorrit De Waele, Yannick Willemen, Ilse Van Brussel, Dorien M Schrijvers, Eva Lion, Evelien L J Smits
Although cancer vaccination has yielded promising results in patients, the objective response rates are low. The right choice of adjuvant might improve the efficacy. Here, we review the biological rationale, as well as the preclinical and clinical results of polyinosinic:polycytidylic acid and its derivative poly-ICLC as cancer vaccine adjuvants. These synthetic immunological danger signals enhanced vaccine-induced anti-tumor immune responses and contributed to tumor elimination in animal tumor models and patients...
February 2015: Pharmacology & Therapeutics
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