69. Combination Therapy of Reovirus and PD-1 Blockade Effectively Establishes Tumor Control Via Innate and Adaptive Immune Responses
Bibliographic record
Abstract
Combination therapy of Reovirus and PD-1 blockade effectively establishes tumor control via innate and adaptive immune responses Karishma Rajani1, Christopher Parrish2, Kevin Shim1, Liz Ilett2, Jill Thompson1, Tim Kottke1, Jose Pulido1, Fiona Errington-Mais2, Peter Selby2, Hardev Pandha3, Kevin Harrington4, Alan Melcher2, Rosa Maria Diaz1, Shane Zaidi1,4 Matt Coffey5, and Richard Vile1,2,6 Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA. 2Leeds Institute of Cancer and Pathology, St. James University Hospital, Leeds, UK. 3University of Surrey, Guildford, UK. 4. The Institute of Cancer Research, 237 Fulham Road, London, SW3.5Oncolytics Biotech Inc., Calgary, Canada. 6Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. Reovirus has oncolytic activity against many human/murine tumor cells, partly because of disruption of the PKR-mediated anti-viral response in malignant cells. We have shown that anti-tumor therapy is directly associated with immune activation by virus replication in tumors. The immune mechanisms of therapy include both innate immune activation against virally infected tumor cells, as well as the generation of adaptive anti tumor immune responses as a result of in vivo priming against tumor associated antigens released during that killing. To exploit the immune components of reovirus anti-tumor therapy, we hypothesized that the combination of reovirus therapy with systemic checkpoint inhibition would augment therapeutic efficacy. To establish this, subcutaneous (SC) B16 melanomas were treated with reovirus alone or in combination with antibody against PD-1. In this model, intra-tumoral (IT) injection of reovirus into SC tumors generated moderate therapy. Systemic treatment of anti-PD-1 antibody along with IT reovirus, significantly enhanced survival compared to IT reovirus alone (p < 0.01) and led to > 40% of mice being cured long term. Immune analysis suggested that the enhanced therapeutic benefit of reovirus plus checkpoint inhibition is contributed by at least two factors. First, blockade of PD-1 significantly enhanced the ability of NK cells to recognize (TNF-α secretion), and kill, reovirus-infected tumor cells. Second, anti PD-1 antibody led to a significant reduction in Treg activity in reovirus-treated mice, with the overall effect of increasing the adaptive CD8+ anti-tumor T cell response. In vivo depletion studies demonstrated that NK cells had a dramatic effect in reducing the therapeutic efficacy of reovirus plus anti-PD-1 therapy. These results indicate that combination therapy of reovirus with PD-1 blockade confers significant survival benefit, by augmenting tumor-specific NK responses and attenuating tumor-specific immunosuppression and is a viable treatment modality with far greater efficacy than either therapy alone.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".