A5069553675- MicroRNA in disease regulation
- Ferroptosis and cancer prognosis
- Cancer-related molecular mechanisms research
- RNA Interference and Gene Delivery
- Herpesvirus Infections and Treatments
- RNA modifications and cancer
- Virus-based gene therapy research
- CAR-T cell therapy research
- Poxvirus research and outbreaks
- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- interferon and immune responses
- Cytokine Signaling Pathways and Interactions
- Immune cells in cancer
- Immunotherapy and Immune Responses
- Acute Myeloid Leukemia Research
- Circular RNAs in diseases
- Cancer Immunotherapy and Biomarkers
- Bacillus and Francisella bacterial research
- Computational Drug Discovery Methods
- Cytomegalovirus and herpesvirus research
- RNA Research and Splicing
- NF-κB Signaling Pathways
- Animal Virus Infections Studies
- HER2/EGFR in Cancer Research
Sanofi (United States)
2014-2023
AVEO Oncology (United States)
2014-2015
University of Massachusetts Chan Medical School
2013
National Institutes of Health
2006-2008
National Institute of Allergy and Infectious Diseases
2006-2008
University of Maryland, College Park
2007-2008
University of Iowa
2003-2004
Local immunotherapy with an mRNA mixture encoding four cytokines mobilizes a systemic antitumor response and promotes tumor eradication.
Previous studies established that vaccinia virus could enter cells by fusion with the plasma membrane at neutral pH. However, low pH triggers of virus-infected cells, a hallmark viruses endosomal route. Here, we demonstrate entry mature virions is accelerated brief low-pH treatment and severely reduced inhibitors acidification, providing evidence for predominant low-pH-dependent pathway. Entry cores into cytoplasm, measured expression firefly luciferase, was increased more than 10-fold...
Abstract Hepatocellular carcinoma (HCC) remains a significant clinical challenge with few therapeutic options available to cancer patients. MicroRNA 21-5p (miR-21) has been shown be upregulated in HCC, but the contribution of this oncomiR maintenance tumorigenic phenotype liver poorly understood. We have developed potent and specific single-stranded oligonucleotide inhibitors miR-21 (anti-miRNAs) used them interrogate dependency on panel cell lines. Treatment anti–miR-21, not mismatch...
Resistance to the BRAF inhibitor vemurafenib poses a significant problem for treatment of BRAFV600E-positive melanomas. It is therefore critical prospectively identify all resistance mechanisms prior their emergence in clinic. The described date do not result from secondary mutations within BRAFV600E. To search possible BRAFV600E that can confer drug resistance, we developed systematic experimental approach involving targeted saturation mutagenesis, selection drug-resistant variants, and...
Based on the observation that wild-type Kaposi's sarcoma-associated herpesvirus (KSHV) DNA can be detected in oral cavity of healthy, immunocompetent individuals, we hypothesized epithelial cells could infected vitro by (WT) KSHV isolated from individuals. Primary (P-EPI) and telomerase-immortalized were generated human gingival tissue then with WT throat wash samples. Markers lytic latent infection cultures 24 h postinfection immunofluorescence confocal microscopic assays. The infectivity...
Mechanisms of unassisted delivery RNA therapeutics, including inhibitors microRNAs, remain poorly understood. We observed that the hepatocellular carcinoma cell line SKHEP1 retains productive free uptake a miR-21 inhibitor (anti-miR-21). Uptake anti-miR-21, but not mismatch (MM) control, induces expression known targets (DDAH1, ANKRD46) and leads to dose-dependent inhibition growth. To elucidate mechanisms sensitivity we conducted an unbiased shRNA screen revealed tumor susceptibility gene...
Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. Several mechanisms innate and acquired resistance to have been defined include mutations MHC I IFNγ signaling pathways. However, such occur low frequency additional yet be elucidated. In an effort better understand blockade, we generated mouse tumor model exhibiting vivo anti-PD-1 antibody MC38 tumors PD-1 following serial passaging. Lack...
Targeted extrahepatic delivery of siRNA remains a challenging task in the field nucleic acid therapeutics. An ideal tool must internalize exclusively into cells interest without affecting silencing activity siRNA. Here, we report use anti-EGFR Nanobodies (trademark Ablynx N.V.) as tools for targeted delivery. A straightforward procedure site-specific conjugation to an engineered C-terminal cysteine residue on Nanobody is described. We show that siRNA-conjugated (Nb-siRNA) retain their...
The proteins encoded by the A56R and K2L genes of vaccinia virus form a heterodimer (A56/K2) have fusion regulatory role as deletion or mutation either causes infected cells to large syncytia spontaneously. Here, we showed that formation is dependent on recently described entry complex (EFC), which are also required for virus-cell low-pH-triggered cell-cell fusion. This finding led us consider A56/K2 might prevent direct indirect interaction with EFC. To test this hypothesis, made panel...
Deletion of the A56R or K2L gene vaccinia virus (VACV) results in spontaneous fusion infected cells to form large multinucleated syncytia. A56 and K2 polypeptides bind one another (A56/K2) together are required for interaction with VACV entry complex (EFC); this association has been proposed prevent cells. At least eight viral comprise EFC, but no information available regarding their interactions either each other A56/K2. Utilizing a panel recombinant VACVs designed repress expression...
7005 Background: SAR’579 is a trifunctional natural killer (NK) cell engager targeting CD123 antigen and co-engaging NKp46 CD16a on NK-cells. facilitates the formation of cytolytic synapse between NK-cells CD123-positive tumor cells leading to NK-cell activation killing. We herein report preliminary safety efficacy data from phase 1/2 trial in patients with relapsed or refractory acute myeloid leukemia (R/R AML), B-cell lymphoblastic high risk-myelodysplasia (NCT05086315). Methods: was...
Many animal viruses induce cells to fuse and form syncytia. For vaccinia virus, this phenomenon is associated with mutations affecting the A56 K2 proteins, which a multimer (A56/K2) on surface of infected cells. Recent evidence that A56/K2 interacts entry/fusion complex (EFC) EFC necessary for syncytium formation furnishes strong connection between virus entry cell fusion. Among important remaining questions are whether can prevent as well cell-cell fusion these two viral proteins sufficient...
The recently described vaccinia virus entry/fusion complex (EFC) comprises at least eight polypeptides that are conserved in all poxviruses. Neither the structure of nor roles individual subunits known. Here we provide evidence for an interaction between H2 and A28 context a infection as well uninfected cells transfected with plasmids expressing corresponding genes. We focused on highly 21-amino acid-segment is flanked by cysteine residues. effect amino acid substitutions within...
The pattern recognition receptor RIG-I plays an important role in the of nonself RNA and antiviral immunity. RIG-I's natural ligand, triphosphate (ppp-RNA), is proposed to be a valuable addition growing arsenal cancer immunotherapy treatment options. In this study, we present comprehensive data validating concept utility with synthetic agonist ppp-RNA for therapy human cancer, melanoma as potential entry indication amenable intratumoral treatment. Using mRNA expression tumors, demonstrate...
The varicella-zoster virus (VZV) gB sequence was re-examined in light of recent knowledge about unusually long signal peptides other herpesviral homologs. Through mutational analysis, the discovery made that authentic initiating methionine for VZV is a codon beginning at genome nucleotide 56,819. total length primary translation product 931 amino acids (aa) with 71-aa sequence. Considering likely cleavage site to be located between Ser 71 and Val 72, mature polypeptide would then 860 prior...
Abstract Cancer immunotherapies with anti-PD-1/PD-L1 checkpoint blockade antibodies have revolutionized the treatment of a wide variety malignancies. However, immunotherapy is ineffective in significant subset patients, or eventually results development resistance relapsed disease. Therefore, future immuno-oncology identification new agents that can be combined to increase depth and breadth therapies. Local intratumoral delivery messenger RNA (mRNA)-based provides an opportunity stimulate...
Abstract Cancer immunotherapy localized to the tumor microenvironment holds great potential promote innate and adaptive immune responses against tumors, while avoiding toxicities related systemic administration of immuno-modulatory therapeutics. Current strategies for tumor-targeted, gene-based delivery therapies face limitations in clinic due suboptimal target expression, anti-vector immunity, unwanted genomic rearrangements other off effects. We developed a highly potent synthetic...
Background: SAR’579 is a trifunctional natural killer (NK) cell engager targeting CD123 antigen and co-engaging NKp46 CD16a on NK-cells. facilitates the formation of cytolytic synapse between NK-cells CD123-positive tumor cells leading to NK-cell activation killing. Aims: To report preliminary safety efficacy data from phase 1/2 trial in patients with relapsed or refractory acute myeloid leukemia (R/R AML), B-cell lymphoblastic high risk-myelodysplasia (NCT05086315). Methods: was...
Abstract In the recent decade several immune checkpoint inhibitors, such as anti-PD1/PD-L1 antibodies, have been approved by regulatory authorities and are actively used in oncology clinical practice. However, these antibodies exhibit durable anti-tumor benefits only a small fraction of cancer patients. A major unmet medical need (IO) is extending therapies to patients who never experience tumor regression (primary resistance) those derive initial benefit before experiencing progression...
Abstract Despite the success of checkpoint blockade immunotherapy, most patients do not respond adequately to treatment and tumors effectively evade T lymphocyte Natural Killer (NK) cell immune surveillance. Within tumor microenvironment, activities cells are regulated by a multitude signals including local cytokine milieu. Intratumoral administration our mRNA cocktail therapy, consisting transcripts encoding for IL-12sc, IFNα2b, IL-15sushi GM-CSF, has induced regression in tumor-bearing...
Abstract Hepatocellular carcinoma (HCC) remains a significant unmet medical need with few therapeutic options available. Micro RNA 21 (miR-21) has been shown to be upregulated in HCC, however, contribution of this onco-miR the maintenance tumorigenic phenotype liver cancer poorly understood. We have developed potent and specific single-stranded oligonucleotide inhibitors miR-21 (anti-miR-21) used them interrogate dependency on panel 20 commercially available HCC cell lines vitro. Upon...