{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:08:38Z","timestamp":1790791718035,"version":"4.1.0"},"reference-count":27,"publisher":"BMJ","issue":"4","license":[{"start":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T00:00:00Z","timestamp":1682294400000},"content-version":"unspecified","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Akamis Bio Ltd","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,3,30]]},"published-print":{"date-parts":[[2023,4]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Novel combination therapies to overcome anti-PD-1 resistance are required. Enadenotucirev, a tumor-selective blood stable adenoviral vector, has demonstrated a manageable safety profile and ability to increase tumor immune-cell infiltration in phase I studies in solid tumors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a phase I multicenter study of intravenous enadenotucirev plus nivolumab in patients with advanced\/metastatic epithelial cancer not responding to standard therapy. Co-primary objectives were safety\/tolerability and maximum tolerated dose and\/or maximum feasible dose (MTD\/MFD) of enadenotucirev plus nivolumab. Additional endpoints included response rate, cytokine responses, and anti-tumor immune responses.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Overall, 51 heavily pre-treated patients were treated, 45\/51 (88%) of whom had colorectal cancer (35\/35 patients with information available were microsatellite instability-low\/microsatellite stable) and 6\/51 (12%) had squamous cell carcinoma of the head and neck. The MTD\/MFD of enadenotucirev plus nivolumab was not reached, with the highest dose level tested (1\u00d710<jats:sup>12<\/jats:sup>\u2009vp day 1; 6\u00d710<jats:sup>12<\/jats:sup>\u2009vp days 3 and 5) shown to be tolerable. Overall, 31\/51 (61%) patients experienced a grade 3\u20134 treatment-emergent adverse event (TEAE), most frequently anemia (12%), infusion-related reaction (8%), hyponatremia (6%), and large intestinal obstruction (6%). Seven (14%) patients experienced serious TEAEs related to enadenotucirev; the only serious TEAE related to enadenotucirev occurring in &gt;1 patient was infusion-related reaction (n=2). Among the 47 patients included in efficacy analyses, median progression-free survival was 1.6 months, objective response rate was 2% (one partial response for 10 months), and 45% of patients achieved stable disease. Median overall survival was 16.0 months; 69% of patients were alive at 12 months. Persistent increases in Th1 and related cytokines (IFN\u03b3, IL-12p70, IL-17A) were seen from ~day 15 in two patients, one of whom had a partial response. Among the 14 patients with matching pre-tumor and post-tumor biopsies, 12 had an increase in intra-tumoral CD8<jats:sup>+<\/jats:sup> T-cell infiltration and 7 had increased markers of CD8 T-cell cytolytic activity.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Intravenously dosed enadenotucirev plus nivolumab demonstrated manageable tolerability, an encouraging overall survival and induced immune cell infiltration and activation in patients with advanced\/metastatic epithelial cancer. Studies of next-generation variants of enadenotucirev (T-SIGn vectors) designed to further re-program the tumor microenvironment by expressing immune-enhancer transgenes are ongoing.<\/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=\"NCT02636036\">NCT02636036<\/jats:ext-link>.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jitc-2022-006561","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T13:55:51Z","timestamp":1682344551000},"page":"e006561","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Safety and efficacy of the tumor-selective adenovirus enadenotucirev, in combination with nivolumab, in patients with advanced\/metastatic epithelial cancer: a phase I clinical trial (SPICE)"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct02636036","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct02636036","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Marwan","family":"Fakih","sequence":"first","affiliation":[{"name":"City of Hope Comprehensive Cancer Center, Duarte, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wael","family":"Harb","sequence":"additional","affiliation":[{"name":"Horizon Oncology Center, Lafayette, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7129-5593","authenticated-orcid":false,"given":"Daruka","family":"Mahadevan","sequence":"additional","affiliation":[{"name":"University of Arizona Cancer Center, Tucson, Arizona, 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