{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,14]],"date-time":"2026-03-14T15:38:00Z","timestamp":1773502680848,"version":"3.50.1"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2020,5,27]],"date-time":"2020-05-27T00:00:00Z","timestamp":1590537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA175386"],"award-info":[{"award-number":["R01CA175386"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA108961"],"award-info":[{"award-number":["R01CA108961"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Diffuse midline glioma, formerly DIPG (diffuse intrinsic pontine glioma), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated (i) whether direct delivery of adenovirus-expressing cluster of differentiation (CD)40 ligand (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and (ii) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Syngeneic gliomas in the brainstems of immunocompetent mice were treated with Ad-CD40L and survival, toxicity, and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-\u039424-CD40L, was tested in human patient\u2013derived diffuse midline gliomas and immunocompetent models.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Expression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intratumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-sequencing analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with interleukin (IL)-6, IL-1\u03b2, and tumor necrosis factor \u03b1. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-\u039424-CD40L, the backbone of which has already entered clinical trials for diffuse midline gliomas. Direct intratumoral injection of rAd-\u039424-CD40L, with systemic blockade of IL-6 and IL-1\u03b2, generated significant numbers of cures with readily manageable toxicity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Virus-mediated delivery of CD40L has the potential to be effective in treating diffuse midline gliomas without obligatory neuroinflammation-associated toxicity.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/neuonc\/noaa126","type":"journal-article","created":{"date-parts":[[2020,5,21]],"date-time":"2020-05-21T19:19:25Z","timestamp":1590088765000},"page":"1757-1770","source":"Crossref","is-referenced-by-count":14,"title":["Ad-CD40L mobilizes CD4 T cells for the treatment of brainstem tumors"],"prefix":"10.1093","volume":"22","author":[{"given":"Phonphimon","family":"Wongthida","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew R","family":"Schuelke","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher B","family":"Driscoll","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Kottke","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill M","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason","family":"Tonne","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cathy","family":"Stone","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda L","family":"Huff","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cynthia","family":"Wetmore","sequence":"additional","affiliation":[{"name":"Center for Cancer and Blood Disorders, Phoenix Children\u2019s Hospital, Phoenix, Arizona, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James A","family":"Davies","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Cardiff, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan L","family":"Parker","sequence":"additional","affiliation":[{"name":"Division of Cancer and Genetics, Cardiff University, Cardiff, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Evgin","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard G","family":"Vile","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA"},{"name":"Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,5,27]]},"reference":[{"issue":"6","key":"2020121802292612400_CIT0001","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1097\/00019052-200112000-00006","article-title":"Brain stem gliomas","volume":"14","author":"Guillamo","year":"2001","journal-title":"Curr Opin Neurol."},{"issue":"8","key":"2020121802292612400_CIT0002","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1093\/neuonc\/nox021","article-title":"Diffuse intrinsic pontine gliomas-current management and new biologic insights. Is there a glimmer of hope?","volume":"19","author":"Cohen","year":"2017","journal-title":"Neuro Oncol."},{"issue":"10","key":"2020121802292612400_CIT0003","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1093\/neuonc\/noz077","article-title":"Immunotherapy for pediatric brain tumors: past and present","volume":"21","author":"Foster","year":"2019","journal-title":"Neuro Oncol."},{"issue":"9","key":"2020121802292612400_CIT0004","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.2174\/138920112800958904","article-title":"Recent clinical experience with oncolytic viruses","volume":"13","author":"Donnelly","year":"2012","journal-title":"Curr Pharm Biotechnol."},{"issue":"1","key":"2020121802292612400_CIT0005","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1186\/s40425-019-0673-2","article-title":"Diverse immunotherapies can effectively treat syngeneic brainstem tumors in the absence of overt toxicity","volume":"7","author":"Schuelke","year":"2019","journal-title":"J Immunother Cancer."},{"key":"2020121802292612400_CIT0006","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1146\/annurev.immunol.22.012703.104533","article-title":"CD40\/CD154 interactions at the interface of tolerance and immunity","volume":"22","author":"Quezada","year":"2004","journal-title":"Annu Rev Immunol."},{"key":"2020121802292612400_CIT0007","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1476-4598-13-85","article-title":"Targeted delivery of CD40L promotes restricted activation of antigen-presenting cells and induction of cancer cell death","volume":"13","author":"Brunekreeft","year":"2014","journal-title":"Mol Cancer."},{"issue":"11","key":"2020121802292612400_CIT0008","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1093\/neuonc\/nov090","article-title":"CD40\/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations against glioma models","volume":"17","author":"Chonan","year":"2015","journal-title":"Neuro Oncol."},{"issue":"8","key":"2020121802292612400_CIT0009","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1007\/s00262-014-1561-8","article-title":"Combination of an agonistic anti-CD40 monoclonal antibody and the COX-2 inhibitor celecoxib induces anti-glioma effects by promotion of type-1 immunity in myeloid cells and T-cells","volume":"63","author":"Kosaka","year":"2014","journal-title":"Cancer Immunol Immunother."},{"issue":"6","key":"2020121802292612400_CIT0010","doi-asserted-by":"crossref","first-page":"4168","DOI":"10.4049\/jimmunol.177.6.4168","article-title":"Killing of normal melanocytes, combined with heat shock protein 70 and CD40L expression, cures large established melanomas","volume":"177","author":"Sanchez-Perez","year":"2006","journal-title":"J Immunol."},{"issue":"4","key":"2020121802292612400_CIT0011","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1089\/hum.2009.143","article-title":"Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus","volume":"21","author":"Galivo","year":"2010","journal-title":"Hum Gene Ther."},{"issue":"1","key":"2020121802292612400_CIT0012","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1186\/s12967-017-1182-z","article-title":"Adenovirus-mediated CD40L gene transfer increases Teffector\/Tregulatory cell ratio and upregulates death receptors in metastatic melanoma patients","volume":"15","author":"Schiza","year":"2017","journal-title":"J Transl Med."},{"issue":"1","key":"2020121802292612400_CIT0013","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1038\/s41467-017-01572-7","article-title":"Intratumoral CD40 activation and checkpoint blockade induces T cell-mediated eradication of melanoma in the brain","volume":"8","author":"Singh","year":"2017","journal-title":"Nat Commun."},{"issue":"6","key":"2020121802292612400_CIT0014","doi-asserted-by":"crossref","first-page":"659","DOI":"10.2144\/000112993","article-title":"Re-engineering adenovirus vector systems to enable high-throughput analyses of gene function","volume":"45","author":"Stanton","year":"2008","journal-title":"Biotechniques."},{"issue":"5","key":"2020121802292612400_CIT0015","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1089\/hum.2015.015","article-title":"Incorporation of peptides targeting EGFR and FGFR1 into the adenoviral fiber Knob domain and their evaluation as targeted cancer therapies","volume":"26","author":"Uusi-Kerttula","year":"2015","journal-title":"Hum Gene Ther."},{"issue":"17","key":"2020121802292612400_CIT0016","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1158\/1078-0432.CCR-18-1089","article-title":"Ad5NULL-A20: a tropism-modified, \u03b1v\u03b26 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies","volume":"24","author":"Uusi-Kerttula","year":"2018","journal-title":"Clin Cancer Res."},{"issue":"4","key":"2020121802292612400_CIT0017","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1111\/j.1750-3639.2010.00468.x","article-title":"Monitoring of tumor growth and post-irradiation recurrence in a diffuse intrinsic pontine glioma mouse model","volume":"21","author":"Caretti","year":"2011","journal-title":"Brain Pathol."},{"key":"2020121802292612400_CIT0018","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.jim.2016.09.002","article-title":"Superior isolation of antigen-specific brain infiltrating T cells using manual homogenization technique","volume":"439","author":"Cumba Garcia","year":"2016","journal-title":"J Immunol Methods."},{"key":"2020121802292612400_CIT0019","doi-asserted-by":"crossref","first-page":"21.4.1","DOI":"10.1002\/0471142735.im2104s103","article-title":"Immunohistochemistry","volume":"103","author":"Hofman","year":"2013","journal-title":"Curr Protoc Immunol."},{"issue":"12","key":"2020121802292612400_CIT0020","doi-asserted-by":"crossref","first-page":"5346","DOI":"10.1182\/blood-2006-10-051318","article-title":"CD4 cells can be more efficient at tumor rejection than CD8 cells","volume":"109","author":"Perez-Diez","year":"2007","journal-title":"Blood."},{"issue":"3","key":"2020121802292612400_CIT0021","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1084\/jem.20091918","article-title":"Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts","volume":"207","author":"Quezada","year":"2010","journal-title":"J Exp Med."},{"issue":"11","key":"2020121802292612400_CIT0022","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.it.2014.09.006","article-title":"Tertiary lymphoid structures in cancer and beyond","volume":"35","author":"Dieu-Nosjean","year":"2014","journal-title":"Trends Immunol."},{"key":"2020121802292612400_CIT0023","doi-asserted-by":"crossref","first-page":"180160","DOI":"10.1038\/sdata.2018.160","article-title":"Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types","volume":"5","author":"He","year":"2018","journal-title":"Sci Data."},{"issue":"3","key":"2020121802292612400_CIT0024","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1083\/jcb.85.3.890","article-title":"Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue","volume":"85","author":"McCarthy","year":"1980","journal-title":"J Cell Biol."},{"issue":"1","key":"2020121802292612400_CIT0025","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/sj.onc.1203251","article-title":"A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo","volume":"19","author":"Fueyo","year":"2000","journal-title":"Oncogene."},{"issue":"5","key":"2020121802292612400_CIT0026","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1212\/WNL.51.5.1250","article-title":"The functional role of tumor suppressor genes in gliomas: clues for future therapeutic strategies","volume":"51","author":"Fueyo","year":"1998","journal-title":"Neurology."},{"issue":"4","key":"2020121802292612400_CIT0027","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.semradonc.2014.06.003","article-title":"The genetic signatures of pediatric high-grade glioma: no longer a one-act play","volume":"24","author":"Diaz","year":"2014","journal-title":"Semin Radiat Oncol."},{"issue":"1","key":"2020121802292612400_CIT0028","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s40425-018-0343-9","article-title":"Cytokine release syndrome","volume":"6","author":"Shimabukuro-Vornhagen","year":"2018","journal-title":"J Immunother Cancer."},{"issue":"1","key":"2020121802292612400_CIT0029","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.neo.2015.12.002","article-title":"A novel mouse model of diffuse intrinsic pontine glioma initiated in Pax3-expressing cells","volume":"18","author":"Misuraca","year":"2016","journal-title":"Neoplasia."},{"key":"2020121802292612400_CIT0030","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1146\/annurev.immunol.16.1.111","article-title":"CD40 and CD154 in cell-mediated immunity","volume":"16","author":"Grewal","year":"1998","journal-title":"Annu Rev Immunol."},{"issue":"2","key":"2020121802292612400_CIT0031","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.coi.2013.01.004","article-title":"The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy","volume":"25","author":"Moran","year":"2013","journal-title":"Curr Opin Immunol."},{"key":"2020121802292612400_CIT0032","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.3389\/fimmu.2017.01905","article-title":"Neuroinflammation: microglia and T cells get ready to tango","volume":"8","author":"Schetters","year":"2017","journal-title":"Front Immunol."},{"issue":"6","key":"2020121802292612400_CIT0033","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/s41568-019-0144-6","article-title":"Tertiary lymphoid structures in the era of cancer immunotherapy","volume":"19","author":"Saut\u00e8s-Fridman","year":"2019","journal-title":"Nat Rev Cancer."},{"issue":"7","key":"2020121802292612400_CIT0034","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1164\/rccm.201309-1611OC","article-title":"Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer","volume":"189","author":"Germain","year":"2014","journal-title":"Am J Respir Crit Care Med."},{"issue":"12","key":"2020121802292612400_CIT0035","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.1158\/1078-0432.CCR-15-2762","article-title":"Tumor-infiltrating plasma cells are associated with tertiary lymphoid structures, cytolytic T-cell responses, and superior prognosis in Ovarian cancer","volume":"22","author":"Kroeger","year":"2016","journal-title":"Clin Cancer Res."},{"issue":"17","key":"2020121802292612400_CIT0036","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.1158\/0008-5472.CAN-11-0431","article-title":"Human solid tumors contain high endothelial venules: association with T- and B-lymphocyte infiltration and favorable prognosis in breast cancer","volume":"71","author":"Martinet","year":"2011","journal-title":"Cancer Res."},{"key":"2020121802292612400_CIT0037","doi-asserted-by":"crossref","first-page":"451","DOI":"10.3389\/fimmu.2016.00451","article-title":"Tertiary lymphoid organs in central nervous system autoimmunity","volume":"7","author":"Mitsdoerffer","year":"2016","journal-title":"Front Immunol."},{"issue":"10","key":"2020121802292612400_CIT0038","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/s41577-018-0044-0","article-title":"CD4+ T cell help in cancer immunology and immunotherapy","volume":"18","author":"Borst","year":"2018","journal-title":"Nat Rev Immunol."},{"issue":"5","key":"2020121802292612400_CIT0039","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1093\/neuros\/nyx507","article-title":"Phase I trial of DNX-2401 for diffuse intrinsic pontine glioma newly diagnosed in pediatric patients","volume":"83","author":"Tejada","year":"2018","journal-title":"Neurosurgery."}],"container-title":["Neuro-Oncology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/neuro-oncology\/advance-article-pdf\/doi\/10.1093\/neuonc\/noaa126\/33423543\/noaa126.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/22\/12\/1757\/34948609\/noaa126.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/neuro-oncology\/article-pdf\/22\/12\/1757\/34948609\/noaa126.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,19]],"date-time":"2020-12-19T05:14:51Z","timestamp":1608354891000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/neuro-oncology\/article\/22\/12\/1757\/5847752"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,27]]},"references-count":39,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,5,27]]},"published-print":{"date-parts":[[2020,12,18]]}},"URL":"https:\/\/doi.org\/10.1093\/neuonc\/noaa126","relation":{},"ISSN":["1522-8517","1523-5866"],"issn-type":[{"value":"1522-8517","type":"print"},{"value":"1523-5866","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,12,1]]},"published":{"date-parts":[[2020,5,27]]}}}