Novel oncolytic chimeric orthopoxvirus causes regression of pancreatic cancer xenografts and exhibits abscopal effect at a single low dose

Abstract

BackgroundPancreatic ductal adenocarcinoma (PDAC) has been increasing by 0.5% per year in the United States. PDAC portends a dismal prognosis and novel therapies are needed. This study describes the generation and characterization of a novel oncolytic chimeric orthopoxvirus for the treatment of pancreatic cancer.MethodsAfter chimerization and high-throughput screening, CF33 was chosen from 100 new chimeric orthopoxvirus isolates for its ability to kill pancreatic cancer cells. In vitro cytotoxicity was assayed in six pancreatic cancer cell lines. In vivo efficacy and toxicity were evaluated in PANC-1 and MIA PaCa-2 xenograft models.ResultsCF33 caused rapid killing of six pancreatic cancer cells lines in vitro, releasing damage-associated molecular patterns, and regression of PANC-1 injected and non-injected distant xenografts in vivo after a single low intratumoral dose of 103 plaque-forming units. Using luciferase imaging, CF33 was noted to preferentially replicate in tumors which corresponds to the low viral titers found in solid organs.ConclusionThe low dose of CF33 required to treat pancreatic cancer in this preclinical study may ease the manufacturing and dosing challenges currently facing oncolytic viral therapy.

A chimeric poxvirus with J2R (thymidine kinase) deletion shows safety and anti-tumor activity in lung cancer models

“…We have previously reported the construction of a chimeric poxvirus CF33 that is more efficient in killing cancer cells than the parental poxviruses [20,21]. Sequence analysis of Fig.…”

“…A previous study by Thorne et al [32] showed that among many different strains of VACVs, WR has the highest replication efficiency and cytotoxic potential in tumor cells. Interestingly, CF33 was found to have higher cytotoxic potential than all its parental viruses, including WR strain, in NCI-60 panel of cancer cell lines [20]. Very recently, Ricorde et al [33] reported the generation of a chimeric poxvirus through recombination among 4 different VACV strains: WR, Wyeth, MVA and Copenhagen.…”

“…CF33 was generated through chimerization among multiple species/strains of poxviruses as described previously [20]. To construct CF33-GFP, a cDNA encoding Emerald (GFP) under the H5 early/late promoter was inserted into CF33 at the J2R locus.…”

“…We previously reported the construction of a chimeric poxvirus (CF33), with enhanced anti-tumor activity, through chimerization among 9 species of orthopoxvirus including multiple strains of VACV [20,21]. Here, for the first time we report the genetic sequence analysis of the CF33 virus.…”

Delivery and Biosafety of Oncolytic Virotherapy

“…Chen et al conducted an experiment using intraperitoneal injection of oHSV-1 to mice, suggesting that the combination of a PD-1 blockade and oHSV-1 may be an effective treatment strategy for childhood softtissue sarcoma (65). Besides, low dose of CF33 was confirmed to treat pancreatic cancer by intraperitoneal injection in vivo experiments (66). Kuryk Due to the large peritoneal area, intraperitoneal injected drugs can be absorbed faster than drugs administered the rough subcutaneous injection but slower than those delivered by intravenous injection.…”