10 results on '"Siegel DL"'
Search Results
2. A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia.
- Author
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Bar KJ, Shaw PA, Choi GH, Aqui N, Fesnak A, Yang JB, Soto-Calderon H, Grajales L, Starr J, Andronov M, Mastellone M, Amonu C, Feret G, DeMarshall M, Buchanan M, Caturla M, Gordon J, Wanicur A, Monroy MA, Mampe F, Lindemuth E, Gouma S, Mullin AM, Barilla H, Pronina A, Irwin L, Thomas R, Eichinger RA, Demuth F, Luning Prak ET, Pascual JL, Short WR, Elovitz MA, Baron J, Meyer NJ, Degnan KO, Frank I, Hensley SE, Siegel DL, and Tebas P
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- Adult, Aged, Antibodies, Viral, Female, Hospitalization, Humans, Immune Tolerance, Immunization, Passive methods, Immunosuppression Therapy, Incidence, Male, Middle Aged, Oxygen therapeutic use, RNA, Viral, Respiration, Artificial, Risk Factors, Treatment Outcome, COVID-19 Serotherapy, COVID-19 therapy, Pneumonia, Viral therapy, SARS-CoV-2
- Abstract
BackgroundAntibody-based strategies for COVID-19 have shown promise in prevention and treatment of early disease. COVID-19 convalescent plasma (CCP) has been widely used but results from randomized trials supporting its benefit in hospitalized patients with pneumonia are limited. Here, we assess the efficacy of CCP in severely ill, hospitalized adults with COVID-19 pneumonia.MethodsWe performed a randomized control trial (PennCCP2), with 80 adults hospitalized with COVID-19 pneumonia, comparing up to 2 units of locally sourced CCP plus standard care versus standard care alone. The primary efficacy endpoint was comparison of a clinical severity score. Key secondary outcomes include 14- and 28-day mortality, 14- and 28-day maximum 8-point WHO ordinal score (WHO8) score, duration of supplemental oxygenation or mechanical ventilation, respiratory SARS-CoV-2 RNA, and anti-SARS-CoV-2 antibodies.ResultsEighty hospitalized adults with confirmed COVID-19 pneumonia were enrolled at median day 6 of symptoms and day 1 of hospitalization; 60% were anti-SARS-CoV-2 antibody seronegative. Participants had a median of 3 comorbidities, including risk factors for severe COVID-19 and immunosuppression. CCP treatment was safe and conferred significant benefit by clinical severity score (median [MED] and interquartile range [IQR] 10 [5.5-30] vs. 7 [2.75-12.25], P = 0.037) and 28-day mortality (n = 10, 26% vs. n = 2, 5%; P = 0.013). All other prespecified outcome measures showed weak evidence toward benefit of CCP.ConclusionTwo units of locally sourced CCP administered early in hospitalization to majority seronegative participants conferred a significant benefit in clinical severity score and 28-day mortality. Results suggest CCP may benefit select populations, especially those with comorbidities who are treated early.Trial RegistrationClinicalTrials.gov NCT04397757.FundingUniversity of Pennsylvania.
- Published
- 2021
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3. CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication.
- Author
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Tebas P, Jadlowsky JK, Shaw PA, Tian L, Esparza E, Brennan AL, Kim S, Naing SY, Richardson MW, Vogel AN, Maldini CR, Kong H, Liu X, Lacey SF, Bauer AM, Mampe F, Richman LP, Lee G, Ando D, Levine BL, Porter DL, Zhao Y, Siegel DL, Bar KJ, June CH, and Riley JL
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- Adult, CD8-Positive T-Lymphocytes immunology, Female, Humans, Male, Middle Aged, Viral Load genetics, Viral Load immunology, Virus Replication drug effects, Virus Replication genetics, Anti-Retroviral Agents administration & dosage, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes transplantation, Gene Editing, HIV Infections genetics, HIV Infections immunology, HIV Infections therapy, HIV-1 physiology, Lymphocyte Transfusion, Receptors, CCR5 genetics, Receptors, CCR5 immunology, Virus Replication immunology
- Abstract
BackgroundWe conducted a phase I clinical trial that infused CCR5 gene-edited CD4+ T cells to determine how these T cells can better enable HIV cure strategies.MethodsThe aim of trial was to develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene-edited CD4+ T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene-edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Δ32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4+ T cells, and whether infusion of 10 billion CCR5-edited CD4+ T cells augmented the HIV-specific immune response.ResultsInfusion of the CD4+ T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 Δ32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific CD8+ T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced CD8+ T cell responses.ConclusionThese findings demonstrate how CCR5 gene-edited CD4+ T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses.REGISTRATIONClinicalTrials.gov NCT02388594.FundingNIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies.
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- 2021
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4. CD19-targeting CAR T cell immunotherapy outcomes correlate with genomic modification by vector integration.
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Nobles CL, Sherrill-Mix S, Everett JK, Reddy S, Fraietta JA, Porter DL, Frey N, Gill SI, Grupp SA, Maude SL, Siegel DL, Levine BL, June CH, Lacey SF, Melenhorst JJ, and Bushman FD
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- Antigens, CD19 genetics, Female, Humans, Male, Antigens, CD19 immunology, Genetic Vectors, Immunotherapy, Adoptive, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell immunology
- Abstract
Chimeric antigen receptor-engineered T cells targeting CD19 (CART19) provide an effective treatment for pediatric acute lymphoblastic leukemia but are less effective for chronic lymphocytic leukemia (CLL), focusing attention on improving efficacy. CART19 harbor an engineered receptor, which is delivered through lentiviral vector integration, thereby marking cell lineages and modifying the cellular genome by insertional mutagenesis. We recently reported that vector integration within the host TET2 gene was associated with CLL remission. Here, we investigated clonal population structure and therapeutic outcomes in another 39 patients by high-throughput sequencing of vector-integration sites. Genes at integration sites enriched in responders were commonly found in cell-signaling and chromatin modification pathways, suggesting that insertional mutagenesis in these genes promoted therapeutic T cell proliferation. We also developed a multivariate model based on integration-site distributions and found that data from preinfusion products forecasted response in CLL successfully in discovery and validation cohorts and, in day 28 samples, reported responders to CLL therapy with high accuracy. These data clarify how insertional mutagenesis can modulate cell proliferation in CART19 therapy and how data on integration-site distributions can be linked to treatment outcomes.
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- 2020
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5. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma.
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Cohen AD, Garfall AL, Stadtmauer EA, Melenhorst JJ, Lacey SF, Lancaster E, Vogl DT, Weiss BM, Dengel K, Nelson A, Plesa G, Chen F, Davis MM, Hwang WT, Young RM, Brogdon JL, Isaacs R, Pruteanu-Malinici I, Siegel DL, Levine BL, June CH, and Milone MC
- Subjects
- Adult, Aged, Autografts, B-Cell Maturation Antigen immunology, Cyclophosphamide adverse effects, Disease-Free Survival, Female, Humans, Male, Middle Aged, Multiple Myeloma genetics, Multiple Myeloma immunology, Multiple Myeloma mortality, Neoplasm Proteins genetics, Neoplasm Proteins immunology, Survival Rate, T-Lymphocytes immunology, T-Lymphocytes pathology, T-Lymphocytes transplantation, Transduction, Genetic, Cyclophosphamide administration & dosage, Immunotherapy, Adoptive, Lymphocyte Depletion, Multiple Myeloma therapy, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen immunology
- Abstract
Background: Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM)., Methods: We conducted a phase I study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required., Results: CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product., Conclusion: CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients., Trial Registration: NCT02546167., Funding: University of Pennsylvania-Novartis Alliance and NIH.
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- 2019
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6. Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma.
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Garfall AL, Stadtmauer EA, Hwang WT, Lacey SF, Melenhorst JJ, Krevvata M, Carroll MP, Matsui WH, Wang Q, Dhodapkar MV, Dhodapkar K, Das R, Vogl DT, Weiss BM, Cohen AD, Mangan PA, Ayers EC, Nunez-Cruz S, Kulikovskaya I, Davis MM, Lamontagne A, Dengel K, Kerr ND, Young RM, Siegel DL, Levine BL, Milone MC, Maus MV, and June CH
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- 2019
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7. Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma.
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Garfall AL, Stadtmauer EA, Hwang WT, Lacey SF, Melenhorst JJ, Krevvata M, Carroll MP, Matsui WH, Wang Q, Dhodapkar MV, Dhodapkar K, Das R, Vogl DT, Weiss BM, Cohen AD, Mangan PA, Ayers EC, Nunez-Cruz S, Kulikovskaya I, Davis MM, Lamontagne A, Dengel K, Kerr ND, Young RM, Siegel DL, Levine BL, Milone MC, Maus MV, and June CH
- Subjects
- Aged, B-Cell Maturation Antigen immunology, Combined Modality Therapy methods, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Immunity, Cellular drug effects, Male, Melphalan administration & dosage, Middle Aged, Multiple Myeloma immunology, Myeloablative Agonists therapeutic use, Receptors, Antigen, T-Cell administration & dosage, Receptors, Antigen, T-Cell immunology, SOXB1 Transcription Factors immunology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Transplantation, Autologous, Treatment Outcome, Antigens, CD19 immunology, Immunotherapy, Adoptive methods, Melphalan therapeutic use, Multiple Myeloma drug therapy, Receptors, Antigen, T-Cell therapeutic use
- Abstract
Background: Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019)., Methods: Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS)., Results: ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently., Conclusion: CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells., Trial Registration: Clinicaltrials.gov identifier NCT02135406., Funding: Novartis, NIH, Conquer Cancer Foundation.
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- 2018
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8. A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation.
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Fuentes RE, Zaitsev S, Ahn HS, Hayes V, Kowalska MA, Lambert MP, Wang Y, Siegel DL, Bougie DW, Aster RH, Myers DD, Stepanova V, Cines DB, Muzykantov VR, and Poncz M
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- Animals, Humans, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Prodrugs pharmacokinetics, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins pharmacokinetics, Recombinant Fusion Proteins pharmacology, Thrombosis blood, Urokinase-Type Plasminogen Activator genetics, Urokinase-Type Plasminogen Activator pharmacokinetics, Blood Platelets metabolism, Drug Delivery Systems methods, Prodrugs pharmacology, Thrombosis drug therapy, Urokinase-Type Plasminogen Activator pharmacology
- Abstract
The use of fibrinolytic agents to prevent new thrombus formation is limited by an increased risk of bleeding due to lysis of hemostatic clots that prevent hemorrhage in damaged blood vessels. We sought to develop an agent that provides thromboprophylaxis without carrying a significant risk of causing systemic fibrinolysis or disrupting hemostatic clots. We previously showed that platelet (PLT) α granule-delivered urokinase plasminogen activator (uPA) is highly effective in preventing thrombosis, while being associated with little systemic fibrinolysis or bleeding. Here, we generated a chimeric prodrug composed of a single-chain version of the variable region of an anti-αIIbβ3 mAb fused to a thrombin-activatable, low-molecular-weight pro-uPA (PLT/uPA-T). PLT/uPA-T recognizes human αIIbβ3 on both quiescent and activated platelets and is enzymatically activated specifically by thrombin. We found that this prodrug binds tightly to human platelets even after gel filtration, has a prolonged half-life in mice transgenic for human αIIb compared with that of uPA-T, and prevents clot formation in a microfluidic system. Importantly, in two murine injury models, PLT/uPA-T did not lyse preexisting clots, even when administration was delayed by as little as 10 minutes, while it concurrently prevented the development of nascent thrombi. Thus, PLT/uPA-T represents the prototype of a platelet-targeted thromboprophylactic agent that selectively targets nascent over preexisting thrombi.
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- 2016
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9. Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with pemphigus cause pathogenicity.
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Yamagami J, Payne AS, Kacir S, Ishii K, Siegel DL, and Stanley JR
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- Amino Acid Sequence, Animals, Desmogleins genetics, Desmogleins immunology, Humans, Molecular Sequence Data, Mutagenesis, Site-Directed, Autoantibodies genetics, Autoantibodies immunology, Complementarity Determining Regions genetics, Complementarity Determining Regions immunology, Pemphigus genetics, Pemphigus immunology, Pemphigus pathology
- Abstract
Pemphigus is a life-threatening autoimmune disease in which antibodies specific for desmogleins (Dsgs) cause loss of keratinocyte cell adhesion and blisters. In order to understand how antibodies cause pathogenicity and whether there are commonalities among antibodies in different patients that could ultimately be used to target specific therapy against these antibodies, we characterized Dsg-specific mAbs cloned by phage display from 3 patients with pemphigus vulgaris and 2 with pemphigus foliaceus. Variable heavy chain gene usage was restricted, but similar genes were used for both pathogenic and nonpathogenic mAbs. However, the heavy chain complementarity-determining region 3 (H-CDR3) of most pathogenic, but not nonpathogenic, mAbs shared an amino acid consensus sequence. Randomization of the H-CDR3 and site-directed mutagenesis indicated that changes in this sequence could block pathogenicity but not necessarily binding. In addition, for 2 antibodies with longer H-CDR3s, a tryptophan was critical for pathogenicity but not binding, a result that is consistent with blocking the tryptophan acceptor site that is thought to be necessary for Dsg-mediated adhesion. These studies indicate that H-CDR3 is critical for pathogenicity of a human autoantibody, that a small region (even 1 amino acid) can mediate pathogenicity, and that pathogenicity can be uncoupled from binding in these antibodies.
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- 2010
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10. Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display.
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Payne AS, Ishii K, Kacir S, Lin C, Li H, Hanakawa Y, Tsunoda K, Amagai M, Stanley JR, and Siegel DL
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- Amino Acid Sequence, Animals, Animals, Newborn, Cadherins immunology, Cells, Cultured, Complementarity Determining Regions genetics, Desmoglein 3, Epidermal Cells, Epidermis metabolism, Epitope Mapping, Humans, Immunoglobulin Variable Region genetics, Immunoglobulin Variable Region immunology, Keratinocytes cytology, Keratinocytes metabolism, Mice, Molecular Sequence Data, Peptide Library, Random Allocation, Sequence Alignment, Antibodies, Monoclonal genetics, Antibodies, Monoclonal immunology, Autoantibodies genetics, Autoantibodies immunology, Pemphigus immunology
- Abstract
Pemphigus is a life-threatening blistering disorder of the skin and mucous membranes caused by pathogenic autoantibodies to desmosomal adhesion proteins desmoglein 3 (Dsg3) and Dsg1. Mechanisms of antibody pathogenicity are difficult to characterize using polyclonal patient sera. Using antibody phage display, we have isolated repertoires of human anti-Dsg mAbs as single-chain variable-region fragments (scFvs) from a patient with active mucocutaneous pemphigus vulgaris. ScFv mAbs demonstrated binding to Dsg3 or Dsg1 alone, or both Dsg3 and Dsg1. Inhibition ELISA showed that the epitopes defined by these scFvs are blocked by autoantibodies from multiple pemphigus patients. Injection of scFvs into neonatal mice identified 2 pathogenic scFvs that caused blisters histologically similar to those observed in pemphigus patients. Similarly, these 2 scFvs, but not others, induced cell sheet dissociation of cultured human keratinocytes, indicating that both pathogenic and nonpathogenic antibodies were isolated. Genetic analysis of these mAbs showed restricted patterns of heavy and light chain gene usage, which were distinct for scFvs with different desmoglein-binding specificities. Detailed characterization of these pemphigus mAbs should lead to a better understanding of the immunopathogenesis of disease and to more specifically targeted therapeutic approaches.
- Published
- 2005
- Full Text
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