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  1. Article ; Online: The cytokine storm-An appropriate, over-reactive response to SARS-CoV-2 or the wrong immune pathway?

    Bellgrau, Donald / Modiano, Jaime F

    Scandinavian journal of immunology

    2020  Volume 93, Issue 3, Page(s) e12979

    MeSH term(s) COVID-19/pathology ; COVID-19/therapy ; Cytokine Release Syndrome/immunology ; Cytokine Release Syndrome/pathology ; Cytokines/blood ; Cytokines/immunology ; Humans ; SARS-CoV-2/immunology ; Th1 Cells/immunology ; Th17 Cells/immunology ; Th2 Cells/immunology
    Chemical Substances Cytokines
    Keywords covid19
    Language English
    Publishing date 2020-10-13
    Publishing country England
    Document type Letter
    ZDB-ID 120476-2
    ISSN 1365-3083 ; 0300-9475
    ISSN (online) 1365-3083
    ISSN 0300-9475
    DOI 10.1111/sji.12979
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 806: Show issues Location:
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  3. Article ; Online: Fas ligand based immunotherapy: A potent and effective neoadjuvant with checkpoint inhibitor properties, or a systemically toxic promoter of tumor growth?

    Modiano, Jaime F / Bellgrau, Donald

    Discovery medicine

    2016  Volume 21, Issue 114, Page(s) 109–116

    Abstract: Fas ligand (FasL, CD95L) is a 40-kDa type II transmembrane protein that binds to Fas (CD95) receptors and promotes programmed cell death. Fas receptors are expressed at higher levels in many tumors than in normal cells; however, systemic administration ... ...

    Abstract Fas ligand (FasL, CD95L) is a 40-kDa type II transmembrane protein that binds to Fas (CD95) receptors and promotes programmed cell death. Fas receptors are expressed at higher levels in many tumors than in normal cells; however, systemic administration of FasL or agonistic anti-Fas antibodies to mice with tumors caused lethal hepatitis. Somewhat paradoxically, elimination of Fas or FasL from tumors also leads to death induced by CD95 receptor/ligand elimination (DICE). At face value, this suggests that Fas signaling not only kills normal cells, but that it also is essential for tumor cell survival. Targeting this pathway may not only fail to kill tumors, but instead may even enhance their growth, leading some to report the demise of Fas ligand in cancer immunotherapy. But, to paraphrase Mark Twain, is this death an exaggeration? Here, we provide a careful examination of the literature exploring the merits of FasL as a novel form of cancer immunotherapy. With local administration using delivery vectors that achieve high levels of expression in the tumor environment, our results indicate that the potential for systemic toxicity is eliminated in higher mammals, and that a systemic anti-tumor response ensues, which delays or prevents progression and simultaneously attacks distant metastases.
    MeSH term(s) Animals ; Cell Cycle Checkpoints ; Cell Proliferation/drug effects ; Fas Ligand Protein/therapeutic use ; Fas Ligand Protein/toxicity ; Graft Rejection/immunology ; Humans ; Immunotherapy ; Neoadjuvant Therapy ; Neoplasms/immunology ; Neoplasms/pathology
    Chemical Substances Fas Ligand Protein
    Language English
    Publishing date 2016-02
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 1944-7930
    ISSN (online) 1944-7930
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Can getting excited over nothing provoke autoimmunity?

    Bellgrau, Donald

    Advances in experimental medicine and biology

    2004  Volume 552, Page(s) 311–316

    MeSH term(s) Animals ; Autoimmune Diseases/pathology ; Cell Proliferation ; Diabetes Mellitus/etiology ; Diabetes Mellitus/immunology ; Genetic Predisposition to Disease ; Humans ; Rats ; Rats, Inbred BB ; T-Lymphocytes/immunology
    Language English
    Publishing date 2004
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2214-8019 ; 0065-2598
    ISSN (online) 2214-8019
    ISSN 0065-2598
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  5. Article ; Online: Construction and Immunogenicity Testing of Whole Recombinant Yeast-Based T-Cell Vaccines.

    King, Thomas H / Guo, Zhimin / Hermreck, Melanie / Bellgrau, Donald / Rodell, Timothy C

    Methods in molecular biology (Clifton, N.J.)

    2016  Volume 1404, Page(s) 529–545

    Abstract: GlobeImmune's Tarmogen(®) immunotherapy platform utilizes recombinant Saccharomyces cerevisiae yeast as a vaccine vector to deliver heterologous antigens for activation of disease-specific, targeted cellular immunity. The vaccines elicit immune-mediated ... ...

    Abstract GlobeImmune's Tarmogen(®) immunotherapy platform utilizes recombinant Saccharomyces cerevisiae yeast as a vaccine vector to deliver heterologous antigens for activation of disease-specific, targeted cellular immunity. The vaccines elicit immune-mediated killing of target cells expressing viral and cancer antigens in vivo via a CD8(+) CTL-mediated mechanism. Tarmogens are not neutralized by host immune responses and can be administered repeatedly to boost antigen-specific immunity. Production of the vaccines yields stable off-the-shelf products that avoid the need for patient-specific manufacturing found with other immunotherapeutic approaches. Tarmogens for the treatment of chronic hepatitis B and C and various cancers were well tolerated and immunogenic in phase 1 and 2 clinical trials encompassing >600 subjects. The platform is being widely utilized in basic vaccine research and the most rapid path to success in these endeavors follows from optimal immunoassay selection and execution. This chapter provides detailed methods for the construction and preclinical immunogenicity testing of yeast-based immunotherapeutic products to support the rapid and efficient use of this versatile technology.
    MeSH term(s) Animals ; Flow Cytometry ; Immunization ; Mice ; Saccharomyces cerevisiae/genetics ; Spleen/immunology ; T-Lymphocytes/cytology ; T-Lymphocytes/immunology ; Vaccines, Synthetic/genetics ; Vaccines, Synthetic/immunology
    Chemical Substances Vaccines, Synthetic
    Language English
    Publishing date 2016-04-13
    Publishing country United States
    Document type Journal Article
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-3389-1_35
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  6. Article ; Online: Whole Recombinant Saccharomyces cerevisiae Yeast Expressing Ras Mutations as Treatment for Patients With Solid Tumors Bearing Ras Mutations: Results From a Phase 1 Trial.

    Cohn, Allen / Morse, Michael A / O'Neil, Bert / Whiting, Samuel / Coeshott, Claire / Ferraro, John / Bellgrau, Donald / Apelian, David / Rodell, Timothy C

    Journal of immunotherapy (Hagerstown, Md. : 1997)

    2018  Volume 41, Issue 3, Page(s) 141–150

    Abstract: We are developing whole, heat-killed, recombinant Saccharomyces cerevisiae yeast, engineered to encode target proteins, which stimulate immune responses against malignant cells expressing those targets. This phase 1 trial, enrolling patients with ... ...

    Abstract We are developing whole, heat-killed, recombinant Saccharomyces cerevisiae yeast, engineered to encode target proteins, which stimulate immune responses against malignant cells expressing those targets. This phase 1 trial, enrolling patients with advanced colorectal or pancreas cancer, was designed to evaluate safety, immunogenicity, response, and overall survival of ascending doses of the GI-4000 series of products, which express 3 different forms of mutated Ras proteins. The study enrolled 33 heavily pretreated subjects (14 with pancreas and 19 with colorectal cancer), whose tumors were genotyped before enrollment to identify the specific ras mutation and thereby to identify which GI-4000 product to administer. No dose limiting toxicities were observed and no subject discontinued treatment due to a GI-4000 related adverse event (AE). The majority of AEs and all fatal events were due to underlying disease progression and AE frequencies were not significantly different among dose groups. GI-4000 was immunogenic, as Ras mutation-specific immune responses were detected on treatment in ∼60% of subjects. No objective tumor responses were observed but based on imaging, clinical status and/or biochemical markers, stable disease was observed in 6 subjects (18%) on day 29, while 1 subject had stable disease at days 57 and 85 follow-up visits. The median overall survival was 3.3 months (95% confidence interval, 2.3-5.3 mo), and 5 subjects survived past the 48-week follow-up period. No significant dose-dependent trends for survival were observed. This first clinical trial in humans with GI-4000 demonstrated a favorable safety profile and immunogenicity in the majority of subjects.
    MeSH term(s) Adult ; Aged ; Biological Therapy/methods ; Biomarkers, Tumor ; Complement Activation ; Female ; Gene Expression ; Gene Expression Regulation, Neoplastic ; Humans ; Immunity ; Male ; Middle Aged ; Mutation ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/immunology ; ras Proteins/genetics
    Chemical Substances Biomarkers, Tumor ; ras Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2018-03-25
    Publishing country United States
    Document type Clinical Trial, Phase I ; Journal Article ; Multicenter Study
    ZDB-ID 1064067-8
    ISSN 1537-4513 ; 1053-8550 ; 1524-9557
    ISSN (online) 1537-4513
    ISSN 1053-8550 ; 1524-9557
    DOI 10.1097/CJI.0000000000000219
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1778: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    ab Jg. 2022: Lesesaal (EG)

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  7. Article ; Online: IL-6-inducing whole yeast-based immunotherapy directly controls IL-12-dependent CD8 T-cell responses.

    Tamburini, Beth A / Kedl, Ross M / Bellgrau, Donald

    Journal of immunotherapy (Hagerstown, Md. : 1997)

    2011  Volume 35, Issue 1, Page(s) 14–22

    Abstract: In current clinical trails, whole yeast-based immunotherapy expressing hepatitis C viral antigens demonstrated statistically significant improvement in end of treatment responses when combined with type I interferon based standard of care, even in ... ...

    Abstract In current clinical trails, whole yeast-based immunotherapy expressing hepatitis C viral antigens demonstrated statistically significant improvement in end of treatment responses when combined with type I interferon based standard of care, even in standard of care resistant patients. Although preclinical data suggest yeast vaccination, such as type I interferon, facilitates CD8 T-cell immunity, the capacity of yeast to generate immunity in patients resistant to type I interferon calls into question the mechanism(s) underpinning the efficacy of this approach. We show yeast and a Toll-like receptor exclusive agonist, Pam3Cys, differ in CD8 T-cell generation when combined with an agonistic CD40 antibody. Although both yeast and PamCys were largely Toll-like receptor dependent, the primary CD8 response generated by yeast was significantly less than Pam3Cys in wild-type hosts even in a CD4 T-cell-deficient setting. In addition, immunization of IL6 mice with yeast produced a 3-fold to 6-fold increased CD8 response while the Pam3Cys response was unaffected. The yeast but not Pam3Cys-driven CD8 response was inhibited in both wild-type and IL-6 hosts by blocking interleukin (IL)-12. In addition, IL6 mice had increased CD86 expression on their dendritic cells after yeast immunization also inhibited by IL-12 blockade. Collectively, our results indicate the CD8 T-cell response to yeast but not Pam3Cys is influenced by IL-6-mediated control of IL-12 critical for dendritic cell activation. To our knowledge this is the first demonstration that yeast directly influence IL-12-associated CD8 T-cell immunity providing an additional route whereby recombinant yeast may provide efficacy independent of type I interferon.
    MeSH term(s) Animals ; CD40 Antigens/immunology ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/pathology ; Cell Differentiation/drug effects ; Cell Differentiation/genetics ; Cell Differentiation/immunology ; Cells, Cultured ; Cysteine/administration & dosage ; Cysteine/analogs & derivatives ; Dendritic Cells/drug effects ; Dendritic Cells/immunology ; Dendritic Cells/metabolism ; Dendritic Cells/pathology ; Immunotherapy/methods ; Interferon Type I/immunology ; Interleukin-12/genetics ; Interleukin-12/immunology ; Interleukin-12/metabolism ; Interleukin-6/genetics ; Interleukin-6/immunology ; Interleukin-6/metabolism ; Lipoproteins/administration & dosage ; Lymphocyte Activation/drug effects ; Lymphocyte Activation/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Saccharomyces cerevisiae/immunology ; Th17 Cells/immunology ; Vaccination
    Chemical Substances CD40 Antigens ; Interferon Type I ; Interleukin-6 ; Lipoproteins ; Interleukin-12 (187348-17-0) ; 2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine (87420-41-5) ; Cysteine (K848JZ4886)
    Language English
    Publishing date 2011-11-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1064067-8
    ISSN 1537-4513 ; 1053-8550 ; 1524-9557
    ISSN (online) 1537-4513
    ISSN 1053-8550 ; 1524-9557
    DOI 10.1097/CJI.0b013e3182356888
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1778: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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  8. Article ; Online: GI-19007, a Novel Saccharomyces cerevisiae-Based Therapeutic Vaccine against Tuberculosis.

    King, Thomas H / Shanley, Crystal A / Guo, Zhimin / Bellgrau, Donald / Rodell, Timothy / Furney, Synthia / Henao-Tamayo, Marcela / Orme, Ian M

    Clinical and vaccine immunology : CVI

    2017  Volume 24, Issue 12

    Abstract: As yet, very few vaccine candidates with activity in animals ... ...

    Abstract As yet, very few vaccine candidates with activity in animals against
    MeSH term(s) Animals ; Antigens, Bacterial/genetics ; Antigens, Bacterial/immunology ; Female ; Gene Transfer Techniques ; Guinea Pigs ; Interferon-gamma/secretion ; Interleukin-17/secretion ; Lung/microbiology ; Lung/pathology ; Mice ; Mice, Inbred C57BL ; Mycobacterium tuberculosis/genetics ; Mycobacterium tuberculosis/immunology ; Post-Exposure Prophylaxis/methods ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/immunology ; Saccharomyces cerevisiae/genetics ; Survival Analysis ; Treatment Outcome ; Tuberculosis/immunology ; Tuberculosis/pathology ; Tuberculosis/prevention & control ; Tuberculosis Vaccines/administration & dosage ; Tuberculosis Vaccines/genetics ; Tuberculosis Vaccines/immunology ; Vaccines, Subunit/administration & dosage ; Vaccines, Subunit/genetics ; Vaccines, Subunit/immunology ; Vaccines, Synthetic/administration & dosage ; Vaccines, Synthetic/genetics ; Vaccines, Synthetic/immunology
    Chemical Substances Antigens, Bacterial ; Interleukin-17 ; Recombinant Fusion Proteins ; Tuberculosis Vaccines ; Vaccines, Subunit ; Vaccines, Synthetic ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2017-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2221082-9
    ISSN 1556-679X ; 1556-6811
    ISSN (online) 1556-679X
    ISSN 1556-6811
    DOI 10.1128/CVI.00245-17
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  9. Article: Animal models of type 1 diabetes: genetics and immunological function.

    Lang, Julie / Bellgrau, Donald

    Advances in experimental medicine and biology

    2004  Volume 552, Page(s) 91–116

    MeSH term(s) Alleles ; Animals ; Diabetes Mellitus, Experimental/genetics ; Diabetes Mellitus, Experimental/immunology ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/immunology ; Disease Models, Animal ; Humans ; Immune System ; Mice ; Mice, Inbred NOD ; Mutation ; Rats ; Rats, Inbred BB ; Transgenes
    Language English
    Publishing date 2004
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2214-8019 ; 0065-2598
    ISSN (online) 2214-8019
    ISSN 0065-2598
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  10. Article: The induction of antigen-specific graft tolerance moves a step closer to the bedside.

    Bellgrau, Donald / Sun, Juan

    Transplantation

    2002  Volume 73, Issue 9, Page(s) 1384–1385

    MeSH term(s) Animals ; Antigens/immunology ; Epitopes ; Liver Transplantation/immunology ; Rats ; Transplantation Tolerance
    Chemical Substances Antigens ; Epitopes
    Language English
    Publishing date 2002-05-15
    Publishing country United States
    Document type Comment ; Journal Article
    ZDB-ID 208424-7
    ISSN 1534-6080 ; 0041-1337
    ISSN (online) 1534-6080
    ISSN 0041-1337
    DOI 10.1097/00007890-200205150-00004
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    Zs.MO 509: Show issues

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