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  • 1
    In: Transplantation and Cellular Therapy, Elsevier BV, Vol. 30, No. 2 ( 2024-02), p. S219-S220
    Materialart: Online-Ressource
    ISSN: 2666-6367
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2024
    ZDB Id: 3056525-X
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 2
  • 3
    Online-Ressource
    Online-Ressource
    Cambridge University Press (CUP) ; 2019
    In:  Journal of Clinical and Translational Science Vol. 3, No. s1 ( 2019-03), p. 21-21
    In: Journal of Clinical and Translational Science, Cambridge University Press (CUP), Vol. 3, No. s1 ( 2019-03), p. 21-21
    Kurzfassung: OBJECTIVES/SPECIFIC AIMS: Overall Research Aim: To develop an iNKT-cell engaging reagent (“CAb”)to induce neuroblastoma-directed cytotoxicity in vitro and in a mouse model of neuroblastoma. Objective 1: Explore the contribution of different GD2 affinities to the cytotoxicity against neuroblastoma cells in vitro. Objective 2: Deteremine whether use of different stimulatory glycolipids (alpha-GalCer vs. C34) alter the activation and cytotoxicity of iNKT cells against neuroblastoma in vitro. Objective 3: To analyze survival of an immunocompetent mouse model of neuroblastoma treated with C34-loaded vs alpha-GalCer-loaded CAb molecule, and to analyze the tumor microenvironment in each treatment condition. METHODS/STUDY POPULATION: CAb molecule will be generated by fusing a CD1d protein to an scFv domain for GD2 using cloning techniques. Previous work by our group has used a streptavidin-biotin system to link CD1d to an antibody against GD2, which is large and immunogenic. Protein expression of this novel fusion protein will occur in HEK293 cells. This new CAb molecule will then be loaded with alpha-GalCer or C34 for use in cytotoxicity and in vivo experiments. Cytotoxicity Assessment: Chromium assays will be used to assess the specific cytotoxicity generated by iNKT cells against neuroblastoma cells in vitro. iNKT cells will be activated by “CAb’s” with relatively high and low affinity for GD2, and also with Alpha-GalCer and C34 glycolipid antigen. flow cytometry will be used to assess for CD107a and Interferon Gamma. Mouse Model of Neuroblastoma: TH-MYCN +/+ mice will be used as an immunocompetent model of neuroblastoma. These mice have the MYCN gene under the control of a tyrosine hydroxylase promoter, and spontaneously develop neuroblastomas by 2 weeks of life which are uniformly fatal by 8 weeks of life. In vivo survival studies will be conducted by injecting CAb of relatively high and low affinity, loaded with glycolipid antigen intraperitonealy into TH-MYCN+/+ mice starting at 2 weeks of age, twice weekly. There will also be a matched negative control. Treatment groups are listed below: 1. alpha-GalCer loaded high-affinity Cab 2. alpha-GalCer loaded low-affinity Cab 3. C34-loaded high-affinity Cab 4. C34-loaded low-affinity Cab 5. Unloaded high-affinity Cab 6. Unloaded low-affinity Cab Enrollment will be 6 mice per group for the survival curves. Tumor Microenvironment analysis: 2 additional mice will be included in each group listed above to be sacrificed 2 weeks into treatment for tumor assessment with flow cytomtetry for iNKT cell, NK cell, T-Lymphocyte frequencies as well as interferon-Gamma expression. RESULTS/ANTICIPATED RESULTS: Objective 1: We expect to find that the highest affinity scFv domains for GD2 result in the greatest amount of cytotoxicity against neuroblastoma cells via iNKT cells. Objective 2: We expect that the C34 molecule will induce the greatest amounts of iNKT cell activation against neuroblastoma cells and higher cytotoxicity against neuroblastoma, which has not been shown previously. Objective 3: We expect to see prolonged survival of mice treated with the high affinity GD2 CAb loaded with C34 or alpha GalCer compared with the low affinity CAb loaded with C34 or alpha GalCer. We also expect that the C34 loaded CAb in both groups will have prolonged survival when compared with the alpha-GalCer loaded CAbs of either affinity. DISCUSSION/SIGNIFICANCE OF IMPACT: iNKT cells have been shown previously to confer an improved prognosis in neuroblastoma and other malignancies. Furthermore, high risk neuroblastomas tend to downregulate expression of a chemokine that attracts iNKT’s to the site of the neuroblastoma. Directing iNKT to the site of neuroblastoma holds promise as an effective immunotherapy option. Our preliminary data demonstrate that CAbs directed against GD2 are capable of exerting cytotoxicity of neuroblastoma in vitro. Furthermore a trend towards prolonged survival has been shown in TH-MYCN mice in early experiments. The development of a novel antibody that has reduced immunogenicity, incorporates a glycolipid antigen that does not induce iNKT cell anergy, and is specific for the GD2 tumor specific antigen has potential to result in increased iNKT-mediate neuroblastoma cytotoxicity and prolonged survival in TH-MYCN+/+ mice.
    Materialart: Online-Ressource
    ISSN: 2059-8661
    Sprache: Englisch
    Verlag: Cambridge University Press (CUP)
    Publikationsdatum: 2019
    ZDB Id: 2898186-8
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 4
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 11, No. 1 ( 2023-01), p. e005957-
    Kurzfassung: Immunocompromised patients are at increased risk of SARS-CoV-2 infections. Patients undergoing chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory B-cell malignancies are uniquely immunosuppressed due to CAR T-mediated B-cell aplasia (BCA). While SARS-CoV-2 mortality rates of 33%–40% are reported in adult CAR T-cell recipients, outcomes in pediatric and young adult CAR T-cell recipients are limited. Methods We created an international retrospective registry of CAR T recipients aged 0–30 years infected with SARS-CoV-2 within 2 months prior to or any time after CAR T infusion. SARS-CoV-2-associated illness was graded as asymptomatic, mild, moderate, or severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C). To assess for risk factors associated with significant SARS-CoV-2 infections (infections requiring hospital admission for respiratory distress or supplemental oxygen), univariate and multivariable regression analyses were performed. Results Nine centers contributed 78 infections in 75 patients. Of 70 SARS-CoV-2 infections occurring after CAR T infusion, 13 (18.6%) were classified as asymptomatic, 37 (52.9%) mild, 11 (15.7%) moderate, and 6 (8.6%) severe COVID-19. Three (4.3%) were classified as MIS-C. BCA was not significantly associated with infection severity. Prior to the emergence of the Omicron variant, of 47 infections, 19 (40.4%) resulted in hospital admission and 7 (14.9%) required intensive care, while after the emergence of the Omicron variant, of 23 infections, only 1 (4.3%) required admission and the remaining 22 (95.7%) had asymptomatic or mild COVID-19. Death occurred in 3 of 70 (4.3%); each death involved coinfection or life-threatening condition. In a multivariable model, factors associated with significant SARS-CoV-2 infection included having two or more comorbidities (OR 7.73, CI 1.05 to 74.8, p=0.048) and age ≥18 years (OR 9.51, CI 1.90 to 82.2, p=0.014). In the eight patients infected with SARS-CoV-2 before CAR T, half of these patients had their CAR T infusion delayed by 15–30 days. Conclusions In a large international cohort of pediatric and young adult CAR-T recipients, SARS-CoV-2 infections resulted in frequent hospital and intensive care unit admissions and were associated with mortality in 4.3%. Patients with two or more comorbidities or aged ≥18 years were more likely to experience significant illness. Suspected Omicron infections were associated with milder disease.
    Materialart: Online-Ressource
    ISSN: 2051-1426
    Sprache: Englisch
    Verlag: BMJ
    Publikationsdatum: 2023
    ZDB Id: 2719863-7
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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