{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:43:39Z","timestamp":1793119419135,"version":"4.5.0"},"reference-count":24,"publisher":"BMJ","issue":"10","license":[{"start":{"date-parts":[[2024,10,15]],"date-time":"2024-10-15T00:00:00Z","timestamp":1728950400000},"content-version":"unspecified","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Akamis Bio Ltd","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2024,9,27]]},"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Tumor-selective oncolytic viral vectors are promising anticancer therapeutics; however, challenges with dosing and potency in advanced\/metastatic cancers have limited efficacy and usage. NG-350A is a next-generation blood-stable adenoviral vector engineered to express an agonist anti-cluster of differentiation (CD)40 antibody without affecting tumor-selectivity and oncolytic potency.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Intravenous and intratumoral (IT) administration of NG-350A was assessed in a phase Ia\/Ib study in patients with metastatic\/advanced epithelial tumors (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT03852511\">NCT03852511<\/jats:ext-link>). Dose-escalation was performed separately for intravenous (four dose levels available, each with infusions on Days 1, 3 and 5 of a 57-day treatment period) and IT (single injection on D1 only or injections on Days 1, 8, 15 and 22) administration. The primary objective was safety and tolerability; secondary objectives included determining a recommended dose, pharmacokinetics, and immunogenicity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In total, 25 heavily pretreated patients received NG-350A (16 with intravenous and 9 with IT administration). Intravenous and IT dosing were both well tolerated, with no evidence of transgene-related or off-target viral toxicity. Intravenous and IT dosing resulted in dose-dependent increases in systemic NG-350A C<jats:sub>max<\/jats:sub>. Despite both routes of administration inducing anti-virus antibodies, sustained persistence of NG-350A in blood samples was observed up to 7 weeks after the last dose, particularly with higher intravenous dose levels. Delivery of NG-350A to tumors was demonstrated in biopsy samples following both routes of administration; a dose-dependent pattern was seen with intravenous infusion, with four patients remaining positive for vector DNA in biopsies at Day 57. Transgene messenger RNA from replicating NG-350A was detected in 5\/12 patients with intravenous treatment and 1\/9 patients with IT injection, and sustained increases in inflammatory cytokines were observed following dosing, particularly with higher intravenous dose levels.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This phase 1a study provided initial proof-of-mechanism for NG-350A, with strong evidence of tumor delivery, viral replication and transgene expression\u2014particularly after intravenous dosing. The lack of transgene-related or off-target viral toxicity was consistent with the highly selective delivery and replication of NG-350A, even after systemic delivery. The efficacy of intravenous-dosed NG-350A will now be evaluated in combination with pembrolizumab (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05165433\">NCT05165433<\/jats:ext-link>), as well as with chemoradiotherapy (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT06459869\">NCT06459869<\/jats:ext-link>).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Trial registration number<\/jats:title>\n                  <jats:p>\n                     <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05165433\">NCT05165433<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT06459869\">NCT06459869<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2024-010016","type":"journal-article","created":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T00:50:31Z","timestamp":1729039831000},"page":"e010016","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["First-in-human clinical outcomes with NG-350A, an anti-CD40 expressing tumor-selective vector designed to remodel immunosuppressive tumor microenvironments"],"prefix":"10.1136","volume":"12","clinical-trial-number":[{"clinical-trial-number":"nct03852511","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05165433","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06459869","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05165433","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct06459869","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03852511","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4803-8513","authenticated-orcid":false,"given":"Aung","family":"Naing","sequence":"first","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danny","family":"Khalil","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4968-3143","authenticated-orcid":false,"given":"Oliver","family":"Rosen","sequence":"additional","affiliation":[{"name":"Clinical, Akamis Bio Inc, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D Ross","family":"Camidge","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Colorado Denver, Denver, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Lillie","sequence":"additional","affiliation":[{"name":"Akamis Bio Ltd, Abingdon, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui-Ru","family":"Ji","sequence":"additional","affiliation":[{"name":"Clinical, Akamis Bio Inc, Cambridge, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Stacey","sequence":"additional","affiliation":[{"name":"Akamis Bio Ltd, Abingdon, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8362-1674","authenticated-orcid":false,"given":"Matthew","family":"Thomas","sequence":"additional","affiliation":[{"name":"Akamis Bio Ltd, Abingdon, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee","family":"Rosen","sequence":"additional","affiliation":[{"name":"Department of Medicine, UCLA Medical Center, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,10,15]]},"reference":[{"key":"2025100304232129000_12.10.e010016.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00507-y"},{"key":"2025100304232129000_12.10.e010016.2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2478\/raon-2022-0002","article-title":"Cancer gene therapy goes viral: viral vector platforms come of age","volume":"56","author":"Bezeljak","year":"2022","journal-title":"Radiol Oncol"},{"key":"2025100304232129000_12.10.e010016.3","unstructured":"IMLYGIC\u00ae (talimogene laherparepvec) prescribing information. 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