Single versus repeated intravenous oncolytic reovirus infusions: Implications for immune modulation and rationalised scheduling of therapy in hepatocellular carcinoma
Bibliographic record
Abstract
Abstract Scheduling of oncolytic virus (OV) therapy has never been correlated with immunological /clinical response. In hepatocellular carcinoma (HCC) patients, where background liver is frequently chronically injured, repeated dosing may have deleterious implications, resulting in off-target immune-mediated 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-fat diet or induced liver fibrosis in the context of abnormal background liver. Furthermore, we assess the potential immune-mediated toxicity of single versus multiple virus infusions in combination with PD-1/PD-L1 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 immune response following virus infusion. Furthermore, without improving therapeutic efficacy, repeated viral dosing leads to an unwanted influx of activated T-cells 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-PD-L1 therapy in limiting tumour growth and extending survival in vivo , whilst simultaneously avoiding undesirable toxicities in background liver, in the context of HCC. Novelty and Impact Statement In solid malignancies, the optimum dosing schedule of oncolytic virotherapy thus far has not been correlated with clinical or immunological response. In hepatocellular carcinoma, background liver is frequently injured and repeated viral infusions may have harmful repercussions, tipping the balance from favourable clinical response to further hepatotoxicity. Here, we provide pivotal data that elucidates a rationalised reovirus dosing regimen, with and without checkpoint inhibition, which ensures therapy whilst limiting damage to compromised background liver.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".