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In hepatocellular carcinoma (HCC) patients, where background liver is frequently chronically injured, repeated dosing may have deleterious implications, resulting in off\u2010target immune\u2010mediated damage, thereby tipping the balance between favourable clinical response and hepatotoxicity. Elucidation of the optimum dosing regime is paramount to ensure therapy, whilst limiting damage to background liver. We expand upon our experience in neoadjuvant OV therapy to compare immunological responses from single versus repeated doses of reovirus in cancer patients. The impact of OV on HCC outcomes was examined in vivo following a high\u2010fat diet or induced liver fibrosis in the context of abnormal background liver. Furthermore, we assess the potential immune\u2010mediated toxicity of single versus multiple virus infusions in combination with PD\u20101\/PD\u2010L1 blockade. Data indicate that a single dose of reovirus is equivalent or superior to repeated doses in achieving: (a) induction of an inflammatory cytokine\/chemokine response; (b) peripheral blood immune cell activation; (c) migration of activated CD8+ CTLs. Repeated doses on consecutive days do not improve the amplitude of the immune response following virus infusion. Furthermore, without improving therapeutic efficacy, repeated viral dosing leads to an unwanted influx of activated T\u2010cells into background liver, alongside elevated liver enzymes associated with aberrant liver function. A single dose of reovirus is as effective as multiple doses when combined with anti\u2010PD\u2010L1 therapy in limiting tumour growth and extending survival in vivo, whilst simultaneously avoiding undesirable toxicities in background liver, in the context of HCC.<\/jats:p>","DOI":"10.1002\/ijc.70386","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T13:07:38Z","timestamp":1771247258000},"page":"3252-3267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Single versus repeated intravenous oncolytic reovirus infusions: Implications for immune modulation and rationalised scheduling of therapy in hepatocellular carcinoma"],"prefix":"10.1002","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5790-9579","authenticated-orcid":false,"given":"Karen J.","family":"Scott","sequence":"first","affiliation":[{"name":"Leeds Institute of Medical Research at St. James's University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma J.","family":"West","sequence":"additional","affiliation":[{"name":"Leeds Institute of Medical Research at St. James's University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca J.","family":"Brownlie","sequence":"additional","affiliation":[{"name":"Leeds Institute of Medical Research at St. James's University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fay","family":"Ismail","sequence":"additional","affiliation":[{"name":"Leeds Institute of Medical Research at St. James's University of Leeds  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christy","family":"Ralph","sequence":"additional","affiliation":[{"name":"Leeds Teaching Hospitals NHS Trust  Leeds UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Heineman","sequence":"additional","affiliation":[{"name":"Oncolytics Biotech Inc.  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