{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T00:15:10Z","timestamp":1793837710918,"version":"4.6.1"},"reference-count":41,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T00:00:00Z","timestamp":1737331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"Netherlands Organization for Health Research and Development (ZonMw) Program Translational Gene Therapy Research","doi-asserted-by":"publisher","award":["43200003"],"award-info":[{"award-number":["43200003"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Oncolytic adenoviruses derived from human serotype 5 (Ad5) are being developed to treat cancer. Treatment efficacy could be affected by pre-existing or induced neutralizing antibodies (NAbs), in particular in repeat administration strategies. Several oncolytic adenoviruses that are currently in clinical development have modified fiber proteins to increase their infectivity. One example is Ad5-\u220624.RGD, which carries a cyclic RGD peptide insert in the fiber protein to allow cell entry via integrins. The effect of anti-Ad5 NAbs on anticancer efficacy could be different for oncolytic adenoviruses with RGD-modified fibers than for unmodified Ad5-based viruses. Here, we determine pre-existing and elicited NAb titers in the serum of patients with glioblastoma who were treated by delivering Ad5-\u220624.RGD to the tumor and to the surrounding tumor-infiltrated brain. We show that intracranial infusion of Ad5-\u220624.RGD induced mainly neutralization of adenovirus native tropism. Infection of cells with RGD-modified virus was significantly less affected. In cerebrospinal fluid, neutralizing activity against RGD-mediated infection remained very low. Thus, the RGD-mediated alternative cell entry route allowed to bypass pre-existing and induced anti-Ad5 neutralization. Interestingly, in the course of these experiments, we discovered that the serum of most humans promotes the uptake of RGD-modified adenovirus in human cells. The until now unidentified infection-stimulating factor seems distinct from serum proteins known to promote Ad5 infection. Together, our work supports the utility of RGD-modified oncolytic adenoviruses for the treatment of cancer in humans. Since these viruses hardly induced neutralization, they seem particularly suitable for repeat administration treatments.<\/jats:p>","DOI":"10.3390\/ijms26020854","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T06:53:32Z","timestamp":1737442412000},"page":"854","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Adenovirus-Neutralizing and Infection-Promoting Activities Measured in Serum of Human Brain Cancer Patients Treated with Oncolytic Adenovirus Ad5-\u220624.RGD"],"prefix":"10.3390","volume":"26","author":[{"given":"Ida H.","family":"van der Meulen-Muileman","sequence":"first","affiliation":[{"name":"Amsterdam UMC location Vrije Universiteit Amsterdam, Medical Oncology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6247-4880","authenticated-orcid":false,"given":"Joana","family":"Amado-Azevedo","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location Vrije Universiteit Amsterdam, Medical Oncology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7745-9029","authenticated-orcid":false,"given":"Martine L. M.","family":"Lamfers","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Kleijn","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander","family":"Idema","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location Vrije Universiteit Amsterdam, Neurosurgery, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands"},{"name":"Brain Tumor Center Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P.","family":"Noske","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location Vrije Universiteit Amsterdam, Neurosurgery, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands"},{"name":"Brain Tumor Center Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens M. F.","family":"Dirven","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor W.","family":"van Beusechem","sequence":"additional","affiliation":[{"name":"Amsterdam UMC location Vrije Universiteit Amsterdam, Medical Oncology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands"},{"name":"Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam Infection and Immunity Institute, Cancer Immunology, 1081 HV Amsterdam, The Netherlands"},{"name":"ORCA Therapeutics BV, Onderwijsboulevard 225, 5223 DE \u2018s-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1158\/1078-0432.CCR-20-1565","article-title":"Evolving Status of Clinical Immunotherapy with Oncolytic Adenovirus","volume":"27","author":"Alemany","year":"2021","journal-title":"Clin. 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