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  • 1
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    Online Resource
    The Association of Baseline Plasma SARS-CoV-2 Nucleocapsid Antigen Level and Outcomes in Patients Hospitalized With COVID-19
    American College of Physicians ; 2022
    In:  Annals of Internal Medicine Vol. 175, No. 10 ( 2022-10), p. 1401-1410
    Details
    In: Annals of Internal Medicine, American College of Physicians, Vol. 175, No. 10 ( 2022-10), p. 1401-1410
    Type of Medium: Online Resource
    ISSN: 0003-4819 , 1539-3704
    URL: Article
    DOI: 10.7326/M22-0924
    RVK:
    XA 23600
    Language: English
    Publisher: American College of Physicians
    Publication Date: 2022
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  • 2
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    Effects of combination treatment with durvalumab plus tremelimumab on the tumor microenvironment in non-small-cell lung carcinoma
    Springer Science and Business Media LLC ; 2022
    In:  Cancer Immunology, Immunotherapy Vol. 71, No. 5 ( 2022-05), p. 1167-1181
    Details
    In: Cancer Immunology, Immunotherapy, Springer Science and Business Media LLC, Vol. 71, No. 5 ( 2022-05), p. 1167-1181
    Abstract: The rapid development of immune checkpoint blockade (ICB) therapies has revolutionized the cancer treatment landscape and brightened the long-term forecast for many cancer patients. However, the specific genomic and proteomic changes in tumors treated with different ICB treatments have yet to be fully characterized. We treated four non-small-cell lung carcinoma (NSCLC) tumor digests ex vivo with the anti-PD-L1 antibody durvalumab (D) alone or in combination with the anti-CTLA-4 antibody tremelimumab (T) to explore changes in gene and protein expression associated with these ICB therapies. All four tumors showed a robust increase in interferon gamma (IFN-γ) production (100–300% higher than isotype control) in both D- and D + T-treated tumors. Three of the four tumors showed additional increases in IFN-γ production with D + T compared with D (40–70%). A substantial reduction in interleukin 10 (IL-10) was also found in three of the four tumors (reduced to 4–8%) in response to D and D + T. Conventional CD4 + /CD8 + populations and T cell activation markers increased after D and D + T treatment. D and D + T upregulated multiple IPA pathways involving T cell activation. D + T resulted in additional upregulation of Th1/Th2 pathways through a different set of genes, as well as greater reduction in genes involved in epithelial-mesenchymal transition (EMT), angiogenesis, and cancer stemness. Our results demonstrated that D + T augmented the effects of D in the microenvironment of this set of NSCLC tumors. The specific impact of D + T on the regulation of EMT, angiogenesis, and cancer stemness warrants further evaluation in a larger set of tumors.
    Type of Medium: Online Resource
    ISSN: 0340-7004 , 1432-0851
    URL: Article
    DOI: 10.1007/s00262-021-03065-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 1458489-X
    detail.hit.zdb_id: 195342-4
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  • 3
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    Safety and tolerability of an anti-CD19 monoclonal antibody, MEDI-551, in subjects with systemic sclerosis: a phase I, randomized, placebo-controlled, escalating single-dose study
    Springer Science and Business Media LLC ; 2016
    In:  Arthritis Research & Therapy Vol. 18, No. 1 ( 2016-12)
    Details
    In: Arthritis Research & Therapy, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2016-12)
    Type of Medium: Online Resource
    ISSN: 1478-6362
    URL: Article
    DOI: 10.1186/s13075-016-1021-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2016
    detail.hit.zdb_id: 2041668-4
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  • 4
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    Anifrolumab efficacy and safety by type I interferon gene signature and clinical subgroups in patients with SLE: post hoc analysis of pooled data from two phase III trials
    BMJ ; 2022
    In:  Annals of the Rheumatic Diseases Vol. 81, No. 7 ( 2022-07), p. 951-961
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 81, No. 7 ( 2022-07), p. 951-961
    Abstract: To characterise the efficacy and safety of anifrolumab in patients with systemic lupus erythematosus (SLE) according to interferon gene signature (IFNGS), demographic and clinical subgroups. Methods We performed post hoc analyses of pooled data from the 52-week phase III TULIP-1/TULIP-2 placebo-controlled trials of intravenous anifrolumab in moderate-to-severe SLE. Outcomes were assessed in predefined subgroups: IFNGS (high/low), age, sex, body mass index, race, geographic region, age of onset, glucocorticoid use, disease activity and serological markers. Results In pooled data, patients received anifrolumab 300 mg (360/726) or placebo (366/726); 82.6% were IFNGS-high. IFNGS-high patients had greater baseline disease activity and were more likely to have abnormal serological markers versus IFNGS-low patients. In the total population, a greater proportion of patients treated with anifrolumab versus placebo achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 52 (difference 16.6%; nominal p 〈 0.001). BICLA response treatment differences with anifrolumab versus placebo were comparable to the total population across most predefined subgroups, including subgroups for baseline glucocorticoid dosage ( 〈 10/≥10 mg/day prednisone/equivalent) and for clinical disease activity (SLE Disease Activity Index 2000 score 〈 10/≥10). Subgroups with larger treatment differences included IFNGS-high patients (18.2%), patients with abnormal baseline serological markers (23.1%) and Asian patients (29.2%). The safety profile of anifrolumab was similar across subgroups. Conclusions Overall, this study supports the consistent efficacy and safety of anifrolumab across a range of patients with moderate-to-severe SLE. In a few subgroups, small sample sizes limited conclusions from being drawn regarding the treatment benefit with anifrolumab. Trial registration number NCT02446912 , NCT02446899 .
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2021-221425
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 1481557-6
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  • 5
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    CYP 3A5 genotypes affect tacrolimus pharmacokinetics and infectious complications in C hinese pediatric liver transplant patients
    Wiley ; 2014
    In:  Pediatric Transplantation Vol. 18, No. 2 ( 2014-03), p. 166-176
    Details
    In: Pediatric Transplantation, Wiley, Vol. 18, No. 2 ( 2014-03), p. 166-176
    Abstract: Little information is available regarding the impact of cytochrome P450 ( CYP ) 3A5 on the metabolism of TAC in infant LTx. Therefore, the CYP 3A5 genotype of Chinese pediatric recipients (intestine) as well as donors (graft liver) was performed for the purpose of establishing an optimal dosage regimen in children. Sixty‐four patients were divided according to CYP 3A5 genotype (expression of *1 allele: EX and NEX ) for each recipient (R) and donor (D), EX ‐R/ EX ‐D (n = 21), EX ‐R/ NEX ‐D (n = 8), NEX ‐R/ EX ‐D (n = 8) and NEX ‐R/ NEX ‐D (n = 27). Results indicated that initial TAC daily dose requirement was higher among EX ‐R/ EX ‐D children compared with those who did not express CYP 3A5 (0.28 ± 0.10 vs. 0.19 ± 0.08 mg/kg/day, p   〈   0.01). CYP 3A5 expression contributed an overall of 38.35% to its C/D ratios, and graft liver was a key determinant. Additionally, the EX ‐R/ EX ‐D group showed significantly higher incidence of infectious complications, lower immune response and was an independent risk factor for the development of infections (odds ratio 3.86, p = 0.025). Donor CYP 3A5 expression partially explains TAC dose requirement, the effect of CYP 3A5 variation may influence clinical outcomes; therefore, monitoring immune response may be important for preventing risks associated with under‐ and over‐immunosuppression.
    Type of Medium: Online Resource
    ISSN: 1397-3142 , 1399-3046
    URL: Issue
    URL: Article
    DOI: 10.1111/petr.2014.18.issue-2
    DOI: 10.1111/petr.12216
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 2008614-3
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  • 6
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    Micro RNA ‐206 induces G 1 arrest in melanoma by inhibition of CDK 4 and C yclin D
    Wiley ; 2014
    In:  Pigment Cell & Melanoma Research Vol. 27, No. 2 ( 2014-03), p. 275-286
    Details
    In: Pigment Cell & Melanoma Research, Wiley, Vol. 27, No. 2 ( 2014-03), p. 275-286
    Abstract: Expression profiling of micro RNA s in melanoma lesional skin biopsies compared with normal donor skin biopsies, as well as melanoma cell lines compared with normal melanocytes, revealed that hsa‐mi R ‐206 was down‐regulated in melanoma (−75.4‐fold, P = 1.7 × 10 −4 ). Mi R ‐206 has been implicated in a large number of cancers, including breast, lung, colorectal, ovarian, and prostate cancers; however, its role in tumor development remains largely unknown, its biologic function is poorly characterized, and its targets affecting cancer cells are largely unknown. Mi R ‐206 reduced growth and migration/invasion of multiple melanoma cell lines. Bioinformatics identified cell cycle genes CDK 2, CDK 4, C yclin C , and C yclin D 1 as strong candidate targets. Western blots and 3′ UTR reporter gene assays revealed that mi R ‐206 inhibited translation of CDK 4, C yclin D 1, and C yclin C . Additionally, hsa‐mi R ‐206 transfection induced G 1 arrest in multiple melanoma cell lines. These observations support hsa‐mi R ‐206 as a tumor suppressor in melanoma and identify C yclin C , C yclin D 1, and CDK 4 as mi R ‐206 targets.
    Type of Medium: Online Resource
    ISSN: 1755-1471 , 1755-148X
    URL: Issue
    URL: Article
    DOI: 10.1111/pcmr.2014.27.issue-2
    DOI: 10.1111/pcmr.12200
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 2425880-5
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  • 7
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    1110. AZD7442 (Tixagevimab/Cilgavimab) Demonstrates Potent In Vitro Activity Against SARS-CoV-2 Spike Variants Identified in Circulation and in Prophylaxis Clinical Studies
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. Supplement_2 ( 2022-12-15)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. Supplement_2 ( 2022-12-15)
    Abstract: AZD7442 is a combination of extended–half-life SARS-CoV-2–neutralizing monoclonal antibodies (tixagevimab/cilgavimab) that bind to distinct epitopes on the SARS-CoV-2 spike protein. In the PROVENT study, a single 300 mg intramuscular dose of AZD7442 demonstrated 77% efficacy for prevention of COVID-19 vs placebo at primary analysis, with 83% efficacy through 6-months follow-up, and was well-tolerated. We report conservation of AZD7442 binding sites and neutralizing activity against pseudotyped virus-like particles (VLPs) harboring spike substitutions identified in surveillance, and clinical SARS-CoV-2 isolates from the PROVENT study. Methods Consensus SARS-CoV-2 whole genome sequences were analyzed from open source databases to identify prevalent spike substitutions within the AZD7442 binding site. Phenotypic analyses determined neutralization susceptibility of pseudotyped VLPs with identified spike substitutions. Genotypic analyses were also performed on SARS-CoV-2 spike sequences from PROVENT study (NCT04625725) participants with RT-PCR-positive symptomatic illness. Results Most residues in tixagevimab (13/17) and cilgavimab (13/19) binding sites were & gt;99% conserved among global SARS-CoV-2 isolates (N=8,373,740 through Apr 19, 2022). In 2021, AZD7442 binding site polymorphisms emerged among circulating strains (prevalence: R346K, 11%; N440K, 22%; G446S, 15%; S477N, 28%; L452R, 43%; T478K, 70%; E484A, 27%; E484K, 3%; Q493R, 27%), but these did not affect AZD7442 in vitro neutralization potency. AZD7442 retained neutralization activity against variants of concern or interest tested, including Omicron BA.2, with moderate reduction observed for Omicron BA.1. By median 6-months follow-up (Aug 29, 2021, data cut-off) in the PROVENT study, there were no AZD7442-resistant substitutions observed in breakthrough SARS-CoV-2 illness visits. Conclusion AZD7442 retained neutralization activity against all SARS-CoV-2 variants of concern or interest evaluated. Binding site substitutions identified in circulation, and in breakthrough SARS-CoV-2 infections following a single 300 mg dose of AZD7442 in the PROVENT study, were not associated with AZD7442 escape. Disclosures Kevin M. Tuffy, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Michael E. Abram, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tiffany L. Roe, B.S., AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Bahar Ahani, BSC, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tyler Brady, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Nicolette Schuko, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Lori Clarke, B.S., AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Carolina Caceres, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tara Kenny, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Virginia Takahashi, B.S., AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tianhui Zhang, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds David E. Tabor, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Gustavo H. Kijak, PharmD PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Elizabeth J. Kelly, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Katie Streicher, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac492.949
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2757767-3
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  • 8
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    1160. Treatment-Emergent Viral Variants in the Phase 3 TACKLE Trial Investigating Efficacy and Safety of AZD7442 (Tixagevimab/Cilgavimab) for the Treatment of Mild to Moderate COVID-19 in Adults
    Oxford University Press (OUP) ; 2022
    In:  Open Forum Infectious Diseases Vol. 9, No. Supplement_2 ( 2022-12-15)
    Details
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 9, No. Supplement_2 ( 2022-12-15)
    Abstract: AZD7442 (tixagevimab/cilgavimab) is a combination of neutralizing monoclonal antibodies (mAbs) that bind to distinct epitopes on the SARS-CoV-2 spike protein, with neutralization activity against variants including Omicron. In the Phase 3 TACKLE study, AZD7442 significantly reduced severe disease progression or death and was well-tolerated through Day 29. Viral evolution during treatment has the potential for resistance selection, such as variants exhibiting reduced mAb binding. We report genotypic analysis and phenotypic characterization of variants identified over 15 days after AZD7442 treatment in TACKLE. Methods In TACKLE (NCT04723394), non-hospitalized adults with mild to moderate COVID19 were randomized and dosed ≤7 days from symptom onset with a single 600-mg AZD7442 dose (2 consecutive intramuscular injections, 300 mg of each antibody; n=452) or placebo (n=451). Next-generation sequencing of the spike gene was performed on SARS-CoV-2 reverse-transcription polymerase chain reaction–positive nasal swabs (at baseline and Days 3, 6, and 15). SARS-CoV-2 lineages were assigned using spike nucleotide sequences. Amino acid substitutions, insertions, and deletions were analyzed at allele fractions (AF, % of sequence reads represented by mutation) ≥25% and 3–25%. Results Baseline spike sequences were available from 744 participants (82.4%) (AZD7442, n=380; placebo, n=364); 87% of sequences corresponded to variants of concern/interest; these were balanced between AZD7442 and placebo groups (Table 1). Treatment-emergent (post-dosing) viral variants were rare, with 11 (4.5%) AZD7442 and 3 (1.3%) placebo participants showing the emergence of ≥1 mutation at tixagevimab/cilgavimab binding sites, with an AF ≥25% (Table 2). At AF 3–25%, treatment-emergent viral variants in the AZD7442 binding site were observed in 16 (6.6%) AZD7442 and 15 (6.5%) placebo participants. Conclusion Following AZD7442 treatment, low levels of SARS-CoV-2 variants bearing mutations at tixagevimab/cilgavimab binding sites were identified. These data indicate that combination of two antibodies creates a high genetic barrier for resistance, supporting the use of mAb combinations that bind to distinct epitopes for the treatment of COVID-19. Disclosures Gustavo H. Kijak, PharmD PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Bahar Ahani, BSC, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Douglas Arbetter, MPH, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tyler Brady, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Fernando Chuecos, BS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Vancheswaran Gopalakrishnan, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tiffany L. Roe, B.S., AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Nicolette Schuko, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds F.D. Richard Hobbs, FMedSci, AstraZeneca: Grant/Research Support|AstraZeneca: Principal investigator|NIHR Applied Research Collaboration, Oxford Thames Valley: Director|Oxford BRC and NIHR MedTech: Investigator|UKRI and NIHR: Grant/Research Support Francisco Padilla, MD, Amgen: Grant/Research Support|Amgen: Personal fees|AstraZeneca: Grant/Research Support|AstraZeneca: Personal fees|Boehringer Ingelheim: Grant/Research Support|Boehringer Ingelheim: Personal fees|Ferrer: Grant/Research Support|Ferrer: Personal fees|Kowa: Grant/Research Support|Kowa: Personal fees|Medix: Grant/Research Support|Medix: Personal fees|Merck Sharp and Dohme: Grant/Research Support|Merck Sharp and Dohme: Personal fees|Novartis: Grant/Research Support|Novartis: Personal fees|Pfizer: Grant/Research Support|Pfizer: Personal fees|Sanofi: Grant/Research Support|Sanofi: Personal fees|Servier: Grant/Research Support|Servier: Personal fees|Silanes: Grant/Research Support|Silanes: Personal fees Elizabeth J. Kelly, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Hugh Montgomery, MD, AstraZeneca: Advisor/Consultant|Millfield Medical Ltd: Advisor/Consultant|UK National Institute for Health Research's Comprehensive Biomedical Research Centre at University College London Hospitals: Grant/Research Support Katie Streicher, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    URL: Article
    DOI: 10.1093/ofid/ofac492.997
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2757767-3
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  • 9
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    Online Resource
    Molecular Characterization of AZD7442 (Tixagevimab-Cilgavimab) Neutralization of SARS-CoV-2 Omicron Subvariants
    American Society for Microbiology ; 2023
    In:  Microbiology Spectrum Vol. 11, No. 2 ( 2023-04-13)
    Details
    In: Microbiology Spectrum, American Society for Microbiology, Vol. 11, No. 2 ( 2023-04-13)
    Abstract: Therapeutic anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) monoclonal antibodies (MAbs) provide immunosuppressed and vulnerable populations with prophylactic and treatment interventions against coronavirus disease 2019 (COVID-19). AZD7442 (tixagevimab-cilgavimab) is a combination of extended-half-life neutralizing MAbs that bind to distinct epitopes on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The Omicron variant of concern carries mutations at 〉 35 positions in the spike protein and has undergone further genetic diversification since its emergence in November 2021. Here, we characterize the in vitro neutralization activity of AZD7442 toward major viral subvariants circulating worldwide during the first 9 months of the Omicron wave. BA.2 and its derived subvariants showed the highest susceptibility to AZD7442, while BA.1 and BA.1.1 showed a lower susceptibility. BA.4/BA.5 had a susceptibility level intermediate between BA.1 and BA.2. Mutagenesis of parental Omicron subvariant spike proteins was performed to establish a molecular model to describe the underlying determinants of neutralization by AZD7442 and its component MAbs. The concurrent mutation of residues at positions 446 and 493, located in the tixagevimab and cilgavimab binding sites, was sufficient to enhance in vitro susceptibility of BA.1 to AZD7442 and its component MAbs to levels similar to the Wuhan-Hu-1+D614G virus. AZD7442 maintained neutralization activity against all Omicron subvariants tested up to and including BA.5. The evolving nature of the SARS-CoV-2 pandemic warrants continuing real-time molecular surveillance and assessment of in vitro activity of MAbs used in prophylaxis against and the treatment of COVID-19. IMPORTANCE MAbs are key therapeutic options for COVID-19 prophylaxis and treatment in immunosuppressed and vulnerable populations. Due to the emergence of SARS-CoV-2 variants, including Omicron, it is vital to ensure that neutralization is maintained for MAb-based interventions. We studied the in vitro neutralization of AZD7442 (tixagevimab-cilgavimab), a cocktail of two long-acting MAbs targeting the SARS-CoV-2 spike protein, toward Omicron subvariants circulating from November 2021 to July 2022. AZD7442 neutralized major Omicron subvariants up to and including BA.5. The mechanism of action responsible for the lower in vitro susceptibility of BA.1 to AZD7442 was investigated using in vitro mutagenesis and molecular modeling. A combination of mutations at two spike protein positions, namely, 446 and 493, was sufficient to enhance BA.1 susceptibility to AZD7442 to levels similar to the Wuhan-Hu-1+D614G ancestral virus. The evolving nature of the SARS-CoV-2 pandemic warrants continuing real-time global molecular surveillance and mechanistic studies of therapeutic MAbs for COVID-19.
    Type of Medium: Online Resource
    ISSN: 2165-0497
    URL: Article
    DOI: 10.1128/spectrum.00333-23
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 2807133-5
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  • 10
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    Online Resource
    Increased CD73 and reduced IFNG signature expression in relation to response rates to anti-PD-1(L1) therapies in EGFR-mutant NSCLC.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. 11505-11505
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 11505-11505
    Abstract: 11505 Background: Anti-PD-1(L1) therapies appear to be less efficacious in NSCLC patients whose tumors have EGFR activating mutations, but the underlying mechanism is poorly understood. We investigated the relationship between Methods: Flow cytometry and/or quantitative PCR were used to evaluate genes and proteins in five NSCLC EGFR mt cell lines and 6 wt lines. Anti-EGFR TKIs gefitinib and osimertinib were used at concentrations ranging from 0.001-100uM; EGF was used at 50 ng/mL. CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating durvalumab (10 mg/kg Q2W) in advanced NSCLC. As of 24OCT16, 304 previously treated patients in CP1108 were enrolled. RNA sequencing was conducted on available tumor specimens from 97 patients in CP1108. CP1108 and TCGA were separated by EGFR status for genomic comparisons. Results: Median CD73 expression was increased 10-fold in EGFR mt NSCLC cell lines (n = 5) compared to wt cell lines (n = 6). EGF induced CD73 protein levels 5-40-fold in 3/6 EGFR wt lines. There was dose-dependent inhibition of CD73 expression (45-70 fold maximum) following treatment with gefitinib or osimertinib in 3/5 mt cell lines and 4/6 wt lines, suggesting a causal relationship between the EGFR pathway and CD73 expression. Consistent with these observations, EGFR mutant tumors had ≥2 fold increased expression of CD73 compared to wt (p 〈 0.05) in TCGA and CP1108 NSCLC adenocarcinoma patients. These EGFR mutants had significantly lower levels of IFNg signature, previously reported to be associated with enhanced benefit from durvalumab. Conclusions: Our findings identify a novel relationship in NSCLC between EGFR pathway activation, expression of the immunosuppressive molecule CD73 and reduced expression of IFNg mRNA signature. These results prompt the hypothesis that over-expression of CD73 in EGFR-mt NSCLC may explain, at least in part, the reduced benefit from anti-PD-1(L1) in this subset of NSCLC, and suggest evaluating anti-CD73 in combination with EGFR TKIs or anti-PD-L1 in EGFR-mt NSCLC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.11505
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
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