MP83-13 ONCOLYTIC VACCINIA VIRUS HAS SIGNIFICANT ACTIVITY AND INDUCES ANTI-TUMOR IMMUNITY IN BLADDER CANCER
Bibliographic record
Abstract
You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology IV1 Apr 2016MP83-13 ONCOLYTIC VACCINIA VIRUS HAS SIGNIFICANT ACTIVITY AND INDUCES ANTI-TUMOR IMMUNITY IN BLADDER CANCER Kyle Potts, Nicole Favis, Chad Irwin, Ronald Moore, David Evans, and Mary Hitt Kyle PottsKyle Potts More articles by this author , Nicole FavisNicole Favis More articles by this author , Chad IrwinChad Irwin More articles by this author , Ronald MooreRonald Moore More articles by this author , David EvansDavid Evans More articles by this author , and Mary HittMary Hitt More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2195AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Most Bladder Cancers (BCs) are diagnosed as non-muscle invasive, however with a recurrence rate of up to 80%, many patients require multiple treatment strategies that often fail. In particular, Bacillus Calmette-Guerin (BCG) carries the risk of infection and can be dangerous for immunocompromised (IC) patients. 30% of patients fail BCG therapy and cystectomy remains the standard treatment in these cases. Oncolytic viruses preferentially replicate in and lyse cancer cells while sparing normal cells. Virus replication requires an abundant supply of dNTPs, but because cellular enzymes that synthesize dNTPs are degraded at the end of S-phase, vaccinia virus (VAC) expresses its own biosynthetic enzymes including both I4L (large, R1) and F4L (small, R2) subunits of the heterodimeric ribonucleotide reductase. We have shown that deleting the F4L gene inhibits virus replication in normal cells and reduces virulence while retaining replication proficiency in cancer cells. METHODS We developed preclinical and clinical grade VACs with deletions in F4L, J2R (viral thymidine kinase) or both. Oncolytic activities of these VACs were evaluated in a panel of human and rodent BC or normal cell lines in vitro. Two BC models were used to assess the VACs in vivo: Syngeneic AY-27 in immunocompetent rats and human RT112-luc xenografts in IC mice. RESULTS Cytotoxicity assays showed a high degree of cell killing in infections with VACs. Highly efficient VAC replication was seen in BC cells with significantly less replication seen in normal cells (p<0.01). VACs selectively replicated in both AY-27 immunocompetent and RT112-luc IC BC models causing significant tumor regression (p<0.001) or complete ablation with no toxicity. Rats treated with the VACs developed a protective CD8+ T-cell mediated anti-tumor immunity, evident by tumor rejection upon challenge and in vitro assays. Finally, VAC replicated in BC cell lines made BCG-refractory. CONCLUSIONS Our data indicate that ΔF4L VACs retain their replication proficiency and cytotoxicity in BC cells despite deletion of these critical viral genes required in non-transformed cells. Significant replication in BC cells that are resistant to the uptake of BCG was observed. Treatment with ΔF4L VACs in vivo is selective for BC cells, elicits an anti-tumor immunity, and shows no signs of toxicity. Further mechanistic investigations are being conducted on the antitumor effects of ΔF4L VACs in a BCG-resistant animal model. If successful VAC could provide an essential line of therapy for patients, particularly those refractory to BCG treatment. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1086 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Kyle Potts More articles by this author Nicole Favis More articles by this author Chad Irwin More articles by this author Ronald Moore More articles by this author David Evans More articles by this author Mary Hitt More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
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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 | 0.000 | 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 | 0.001 |
| 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".