A5063908914- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- Monoclonal and Polyclonal Antibodies Research
- CAR-T cell therapy research
- HIV Research and Treatment
- Phagocytosis and Immune Regulation
- RNA Interference and Gene Delivery
- T-cell and B-cell Immunology
- Cytomegalovirus and herpesvirus research
- Virus-based gene therapy research
- Adenosine and Purinergic Signaling
- Glycosylation and Glycoproteins Research
- HIV/AIDS drug development and treatment
- Immune cells in cancer
- Extracellular vesicles in disease
- Erythrocyte Function and Pathophysiology
- Atherosclerosis and Cardiovascular Diseases
- Chemokine receptors and signaling
- RNA Research and Splicing
- Cutaneous lymphoproliferative disorders research
- Lymphoma Diagnosis and Treatment
- Herpesvirus Infections and Treatments
- Complement system in diseases
- Genetics and Neurodevelopmental Disorders
Lemuel Shattuck Hospital
2018-2024
The Ohio State University
2011-2018
Heat Biologics (United States)
2016-2017
Albert Einstein College of Medicine
2014
University of Rochester Medical Center
2010-2011
University of Rochester
2007-2010
Abstract Background SAMHD1 is an HIV-1 restriction factor in non-dividing monocytes, dendritic cells (DCs), macrophages, and resting CD4 + T-cells. Acting as a deoxynucleoside triphosphate (dNTP) triphosphohydrolase, hydrolyzes dNTPs restricts infection macrophages T-cells by decreasing the intracellular dNTP pool. However, pool DCs its regulation remain unclear. has been reported type I interferon (IFN)-inducible protein, but whether IFNs upregulate expression primary T-lymphocytes unknown....
ABSTRACT Human and mouse SAMHD1 proteins block human immunodeficiency virus type 1 (HIV-1) infection in noncycling monocytic cells by reducing the intracellular deoxynucleoside triphosphate (dNTP) concentrations. Phosphorylation of at threonine 592 (T592) cyclin-dependent kinase (CDK1) cyclin A2 impairs its HIV-1 restriction activity, but not dNTP hydrolase suggesting that depletion is sole mechanism SAMHD1-mediated restriction. Using coimmunoprecipitation mass spectrometry, we identified...
The retrovirus restriction factor SAMHD1 is the first identified mammalian dNTP triphosphohydrolase that highly expressed in human myeloid lineage cells and CD4(+) T lymphocytes. Although expression variable cell lines tissue types, mechanisms underlying gene regulation have not been defined. Recent studies showed primary lymphocytes, but some lines. Here, we report varies among four transcriptionally regulated. Cloning sequence analysis of promoter revealed a CpG island methylated (such as...
Simultaneous blockade of immune checkpoint molecules and co-stimulation the TNF receptor superfamily (TNFRSF) is predicted to improve overall survival in human cancer.TNFRSF depends upon coordinated antigen recognition through T cell followed by homotrimerization TNFRSF, most effective when these functions occur simultaneously.To address this mechanism, we developed a two-sided fusion protein incorporating extracellular domains (ECD) PD-1 OX40L, adjoined central Fc domain, termed...
Disrupting the binding of CD47 to SIRPα has emerged as a promising immunotherapeutic strategy for advanced cancers by potentiating antibody-dependent cellular phagocytosis (ADCP) targeted antibodies. Preclinically, CD47/SIRPα blockade induces antitumor activity increasing tumor cells macrophages and enhancing cross-presentation antigens CD8+ T dendritic cells; both these processes are potentiated CD40 signaling. Here we generated novel, two-sided fusion protein incorporating extracellular...
Vγ9Vδ2+ T cell-targeted immunotherapy is of interest to harness its MHC-independent cytotoxic potential against a variety cancers. Recent studies have identified heterodimeric butyrophilin (BTN) 2A1 and BTN3A1 as the molecular entity providing "signal 1" Vγ9Vδ2 TCR, but 2" costimulatory requirements remain unclear. Using tumor cell-free assay, we demonstrated that BTN2A1/3A1 fusion protein activated human cells, only in presence signal via CD28 or NK group 2 member D. Nonetheless, addition...
Cross-species transmission and adaptation of simian immunodeficiency viruses (SIVs) to humans have given rise human (HIVs). HIV type 1 (HIV-1) 2 (HIV-2) were derived from SIVs that infected chimpanzee (SIVcpz) sooty mangabey (SIVsm), respectively. The HIV-1 restriction factor SAMHD1 inhibits infection in myeloid cells can be counteracted by the Vpx protein HIV-2 SIVsm lineage. However, its ancestor SIVcpz do not encode a has evolved mechanism overcome SAMHD1-mediated restriction. Here we...
Lipid nanoparticle (LNP)-encapsulated mRNA has been used for in vivo production of several secreted protein classes, such as IgG, and enabled the development personalized vaccines oncology. Establishing feasibility delivering complex multispecific modalities that require higher-order structures important their function could help expand use mRNA/LNP biologic formulations. Here, we evaluated whether administration formulations SIRPα-Fc-CD40L TIGIT-Fc-LIGHT achieve oligomerization extend...
The Vpr protein of human immunodeficiency virus type 1 (HIV-1) contributes to viral replication in non-dividing cells, specifically those the myeloid lineage. However, effects enhancing HIV-1 infection dendritic cells have not been extensively investigated. Here, we evaluated role during highly permissive peripheral blood mononuclear (PBMCs) and CD4(+) T-cells compared it that monocyte-derived (MDDCs), which are less susceptible infection. Infections dividing PBMCs MDDCs were carried out...
Abstract T-cell costimulation typically occurs in a defined microenvironment that is not recapitulated by agonistic antibody therapy. To deliver such stimulation under more favorable conditions, we investigated whether an allogeneic cell-based vaccine secreted Fc-OX40L, Fc-ICOSL, or Fc-4-1BBL would activate and expand T cells comparably with systemically administered agonist antibodies. Among these costimulators, locally Fc-OX40L provided superior priming of antigen-specific CD8+ cells,...
Abstract Coinhibition of TIGIT (T cell immunoreceptor with Ig and ITIM domains) PD-1/PD-L1 (PD-1/L1) may improve response rates compared monotherapy PD-1/L1 blockade in checkpoint naive non–small lung cancer PD-L1 expression >50%. mAbs an effector-competent Fc can induce myeloid activation, some have demonstrated effector T depletion, which carries a clinical liability unknown significance. Ab translates to antitumor activity by enabling PVR signaling through CD226 (DNAM-1), be...
Abstract Vγ9Vδ2+ T cell (GDT) targeted immunotherapy is of interest to harness its MHC-independent cytotoxic potential promote anti-tumor immunity. However, it remains unclear whether GDT (1-5% total cells) are present at sufficient numbers be therapeutically relevant. Accumulation intracellular phosphoantigens promotes heterodimerization butyrophilin (BTN) 2A1 and BTN3A1 on the surface, leading TCR-mediated activation GDT. To date, clinical trials in cancer patients have failed demonstrate...
Human immunodeficiency virus type 1 (HIV-1) latency is a major barrier to cure of AIDS. Latently infected cells harbor an integrated HIV-1 genome but are not actively producing HIV-1. Histone deacetylase (HDAC) inhibitors, such as vorinostat (SAHA), have been shown reactivate latent AR-42, modified HDAC inhibitor, has demonstrated efficacy against malignant melanoma, meningioma, and acute myeloid leukemia currently used in clinical trials for non-Hodgkin's lymphoma multiple myeloma. In this...
The development of the integration-competent, herpes simplex virus/Sleeping Beauty (HSV/SB) amplicon vector platform has created a means to efficiently and stably deliver therapeutic transcription units (termed “transgenons”) neurons within mammalian brain. Furthermore, an investigation into transposition capacity HSV/SB system revealed that genome provides optimal substrate for transgenons at least 12 kb in length [de Silva, S., Mastrangelo, M.A., Lotta, L.T., Jr., Burris, C.A., Federoff,...
The Sleeping Beauty (SB) transposon system has been successfully used as a gene delivery tool in nonviral and viral vector platforms. Since its initial reconstruction, series of hyperactive mutants SB have generated. Questions remain to whether the enhanced vitro activities these transposase translate vivo setting, such increased integration efficiencies will ultimately compromise safety profile platform by raising risk genomic insertional mutagenesis. Herein, we compared impact herpes...
Abstract There is considerable interest in therapeutically engaging human γδ T cells. However, due to the unique TCRs of cells, studies from animal models have provided limited directly applicable insights, and cells key immunological tissues remain poorly characterized. In this study, we investigated spleen tissue. Compared blood, where Vδ2+Vγ9+ are dominant subset, splenic included a variety TCR types, with Vδ1+ typically being most frequent. Intracellular cytokine staining revealed that...
Abstract The herpes simplex virus (HSV)‐derived amplicon vector has evolved into a promising gene transfer platform for widespread DNA delivery in replacement strategies and vaccine development given its ease of molecular manipulation, large transgene capacity, transduction efficiencies numerous cell types vivo . recent helper virus‐free packaging methodologies bodes well this system eventual implementation as clinically viable therapeutic modality. For realization clinical application,...
<div>Abstract<p>Lipid nanoparticle (LNP)–encapsulated mRNA has been used for <i>in vivo</i> production of several secreted protein classes, such as IgG, and enabled the development personalized vaccines in oncology. Establishing feasibility delivering complex multispecific modalities that require higher-order structures important their function could help expand use mRNA/LNP biologic formulations. Here, we evaluated whether administration formulations SIRPα-Fc-CD40L...