St Jude Childrens Research Hospital | Date: 2016-11-04
Methods for regulating T cell function in a subject, particularly regulatory T cell activity are provided. Methods of the invention include administering to a subject a therapeutically effective amount of an Interleukin 35-specific binding agent, such as an antibody or small molecule inhibitor. The invention further provides methods for enhancing the immunogenicity of a vaccine or overcoming a suppressed immune response to a vaccine in a subject, including administering to the subject a therapeutically effective amount of an IL35-specific binding agent and administering to the subject a vaccine. In one embodiment the vaccine is a cancer vaccine.
Ucl Business Plc and St Jude Childrens Research Hospital | Date: 2016-09-01
There is provided a nucleic acid molecule comprising a nucleotide sequence encoding for a functional factor VIII protein, wherein the portion of the nucleotide sequence encoding for the B domain of the factor VIII protein is between 90 and 111 nucleotides in length and encodes for an amino acid sequence comprising a sequence having at least 85% identity to SEQ ID NO: 4 and which comprises six asparagine residues. Also provided is a functional factor VIII protein, a vector comprising the above nucleic acid molecule, a host cell, a transgenic animal, a method of treating haemophilia, e.g. haemophilia A, and a method for the preparation of a parvoviral gene delivery vector.
Sloan Kettering Cancer Center and St Jude Childrens Research Hospital | Date: 2017-02-08
A method of determining sensitivity to cancer treatment includes the step of determining the presence of overexpression of MYC in a biological sample from a patient suffering from cancer, wherein the presence of overexpression of MYC indicates a sensitivity to a treatment by a CDK9 inhibitor and wherein the cancer is selected from the group consisting of carcinoma, leukemia, and lymphoma.
St Jude Childrens Research Hospital | Date: 2016-11-28
The invention is directed to treatment of cancer, infections and various inflammatory and autoimmune conditions by affecting regulatory T cell stability and function via a Neuropilin-1:Semaphorin axis.
National University of Singapore and St Jude Childrens Research Hospital | Date: 2017-03-22
The present invention provides, in certain aspects, a natural killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15), and methods for producing such cells. The invention further provides methods of using a natural killer (NK) cell that expresses all or a functional portion of interleukin-15 (IL-15) to treat cancer in a subject or to enhance expansion and/or survival of NK cells.
Mount Sinai School of Medicine, St Jude Childrens Research Hospital and The United States Of America | Date: 2016-12-12
The present invention relates, in general, to attenuated swine influenza viruses having an impaired ability to antagonize the cellular interferon (IFN) response, and the use of such attenuated viruses in vaccine and pharmaceutical formulations. In particular, the invention relates to attenuated swine influenza viruses having modifications to a swine NS1 gene that diminish or eliminate the ability of the NS1 gene product to antagonize the cellular IFN response. These viruses replicate in vivo, but demonstrate decreased replication, virulence and increased attenuation, and therefore are well suited for use in live virus vaccines, and pharmaceutical formulations.
Kanneganti T.-D.,St Jude Childrens Research Hospital
Nature Reviews Immunology | Year: 2010
The immune response to viral infections is determined by a complex interplay between the pathogen and the host. Innate immune cells express a set of cytosolic sensors to detect viral infection. Recognition by these sensors induces the production of type I interferons and the assembly of inflammasome complexes that activate caspase-1, leading to production of interleukin-1β (IL-1β) and IL-18. Here, I discuss recent progress in our understanding of the central roles of NOD-like receptors (NLRs) and inflammasomes in the immune response during viral infections. This information will improve our understanding of host defence mechanisms against viruses and provide new avenues for interfering in the pathogenesis of infectious diseases. © 2010 Macmillan Publishers Limited. All rights reserved.
McKinnon P.J.,St Jude Childrens Research Hospital
Annual Review of Pathology: Mechanisms of Disease | Year: 2012
Ataxia telangiectasia (A-T) results from inactivation of the ATM protein kinase. DNA-damage signaling is a prime function of this kinase, although other roles have been ascribed to ATM. Identifying the primary ATM function(s) for tissue homeostasis is key to understanding how these functions contribute to the prevention of A-T-related pathology. In this regard, because A-T is primarily a neurodegenerative disease, it is essential to understand how ATM loss results in degenerative effects on the nervous system. In addition to delineating the biochemistry and cell biology of ATM, important insights into the molecular basis for neurodegeneration in A-T come from a spectrum of phenotypically related neurodegenerative diseases that directly result from DNA-repair deficiency. Together with A-T, these syndromes indicate that neurodegeneration can be caused by the failure to appropriately respond to DNA damage. This review focuses on defective DNA-damage signaling as the underlying cause of A-T. Copyright ©2012 by Annual Reviews. All rights reserved.
Zimmerman E.I.,St Jude Childrens Research Hospital
Blood | Year: 2013
FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcomes. Although initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD-positive patients, subsequent relapse often occurs upon acquisition of secondary FLT3 kinase domain (KD) mutations, primarily at residues D835 and F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties and is active against FLT3 containing ITD and/or D835- or F691-activating mutations. Potent activity was observed in FLT3-ITD-positive AML cell lines. Crenolanib delayed the outgrowth of MV4-11 cells in a xenograft mouse model, whereas in combination with the type II TKI sorafenib, a significant decrease in leukemic burden (P < .001) and prolonged survival (P < .01) was observed compared with either type I or II TKI alone. Crenolanib was active against Ba/F3 cells harboring FLT3-ITD and secondary KD mutations and sorafenib-resistant MOLM-13 cells containing FLT3-ITD/D835Y both in vitro and in vivo. In addition, crenolanib inhibited drug-resistant AML primary blasts with FLT3-ITD and D835H/Y mutations. These preclinical data demonstrate that crenolanib is effective against FLT3-ITD containing secondary KD mutations, suggesting that crenolanib may be a useful therapeutic agent for TKI-naive and drug-resistant FLT3-ITD-positive AML.
Robison L.L.,St Jude Childrens Research Hospital |
Hudson M.M.,St Jude Childrens Research Hospital
Nature Reviews Cancer | Year: 2014
Survival rates for most paediatric cancers have improved at a remarkable pace over the past four decades. In developed countries, cure is now the probable outcome for most children and adolescents who are diagnosed with cancer: their 5-year survival rate approaches 80%. However, the vast majority of these cancer survivors will have at least one chronic health condition by 40 years of age. The burden of responsibility to understand the long-term morbidity and mortality that is associated with currently successful treatments must be borne by many, including the research and health care communities, survivor advocacy groups, and governmental and policy-making entities.