دورية أكاديمية
أعرض في EDS

Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models.

التفاصيل البيبلوغرافية
العنوان: Immunotoxin-αCD40 therapy activates innate and adaptive immunity and generates a durable antitumor response in glioblastoma models.
المؤلفون: Parker S; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA., McDowall C; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA., Sanchez-Perez L; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA., Osorio C; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA., Duncker PC; Cytek Biosciences Inc., Fremont, CA 94538, USA., Briley A; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA., Swartz AM; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA., Herndon JE 2nd; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC 27710, USA., Yu YA; Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., McLendon RE; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA., Tedder TF; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA., Desjardins A; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA., Ashley DM; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA., Gunn MD; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.; Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA., Enterline DS; Department of Radiology, Duke University Medical Center, Durham, NC 27710, USA., Knorr DA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Pastan IH; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Nair SK; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA., Bigner DD; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA., Chandramohan V; Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
المصدر: Science translational medicine [Sci Transl Med] 2023 Feb 08; Vol. 15 (682), pp. eabn5649. Date of Electronic Publication: 2023 Feb 08.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Intramural
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Association for the Advancement of Science
مواضيع طبية MeSH: Glioblastoma*/pathology , Immunotoxins*/genetics , Glioma* , Brain Neoplasms*/therapy, Humans ; Animals ; Mice ; CD8-Positive T-Lymphocytes ; Adaptive Immunity ; ErbB Receptors/metabolism ; Cell Line, Tumor
مستخلص: D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-IT+αCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8 + T cell immunity, and generated cures. D2C7-IT+αCD40 treatment increased intratumoral Slamf6 + CD8 + T cells with a progenitor phenotype and decreased terminally exhausted CD8 + T cells. D2C7-IT+αCD40 treatment stimulated intratumoral CD8 + T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. Tumor transcriptome profiling established CD40 up-regulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.
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معلومات مُعتمدة: K08 CA248966 United States CA NCI NIH HHS; R01 NS119183 United States NS NINDS NIH HHS; R35 CA197264 United States CA NCI NIH HHS
سلسلة جزيئية: ClinicalTrials.gov NCT04547777
المشرفين على المادة: 0 (Immunotoxins)
EC 2.7.10.1 (ErbB Receptors)
تواريخ الأحداث: Date Created: 20230208 Date Completed: 20230210 Latest Revision: 20230909
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10440725
DOI: 10.1126/scitranslmed.abn5649
PMID: 36753564
قاعدة البيانات: MEDLINE
الوصف
تدمد:1946-6242
DOI:10.1126/scitranslmed.abn5649