Effects of capsid‐modified oncolytic adenoviruses and their combinations with gemcitabine or silica gel on pancreatic cancer

Abstract

Conventional cancer treatments often have little impact on the course of advanced pancreatic cancer. Although cancer gene therapy with adenoviruses is a promising developmental approach, the primary receptor is poorly expressed in pancreatic cancers which might compromise efficacy and thus targeting to other receptors could be beneficial. Extended stealth delivery, combination with standard chemotherapy or circumvention of host antiadenoviral immune response might improve efficacy further. In this work, capsid-modified adenoviruses were studied for transduction of cell lines and clinical normal and tumor tissue samples. The respective oncolytic viruses were tested for oncolytic activity in vitro and in vivo. Survival was studied in a peritoneally disseminated pancreas cancer model, with or without concurrent gemcitabine while silica implants were utilized for extended intraperitoneal virus delivery. Immunocompetent mice and Syrian hamsters were used to study the effect of silica mediated delivery on antiviral immune responses and subsequent in vivo gene delivery. Capsid modifications selectively enhanced gene transfer to malignant pancreatic cancer cell lines and clinical samples. The respective oncolytic viruses resulted in increased cell killing in vitro, which translated into a survival benefit in mice. Early proinfammatory cytokine responses and formation of antiviral neutralizing antibodies was partially avoided with silica implants. The implant also shielded the virus from pre-existing neutralizing antibodies, while increasing the pancreas/liver gene delivery ratio six-fold. In conclusion, capsid modified adenoviruses would be useful for testing in pancreatic cancer trials. Silica implants might increase the safety and efficacy of the approach.Pancreatic cancer is one of the most aggressive human solid tumors. Typical features include rapid growth and early metastatic spread, resulting in a 98% mortality to incidence ratio. 1 As over 80% of patients are diagnosed at an advanced stage, curative treatments are rarely possible. Thus, there is need for identifying novel agents with activity in pancreatic cancers.

Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances

“…Both gemcitabine and CPA can decrease neutralizing antibodies in cancer patients 29. An increase in antitumor activity was seen with a wide array of OVs in combination with gemcitabine, including adenovirus,38–44 parvovirus,32,33 reovirus,30,37 VSV,35 HSV,31 vaccinia,45 and myxoma virus 36. Gemcitabine alone fails to trigger HMGB1 release; in contrast, parvovirus does induce HMGB1 32.…”

Win or loss? Combination therapy does improve the oncolytic virus therapy to pancreatic cancer

“…It has a potent antitumor effect against PC without damaging normal tissue [ 31 ]. As gemcitabine has been well investigated in combination with many OVs in PC, HF10 and gemcitabine could be an ideal therapy against PC with minimal side effects [ 32 , 33 ]. A phase I trial aimed to evaluate the safety and effectiveness of HF10 combined with erlotinib and gemcitabine in unresectable PC [ 4 ].…”

Genomic Signature of the Natural Oncolytic Herpes Simplex Virus HF10 and Its Therapeutic Role in Preclinical and Clinical Trials

“…Gemcitabine (GEM) inhibits MDSCs and enhances antitumor immune responses through T cell expansion (51). To date, GEM has been extensively investigated in combination with many OVs in different malignancies, including pancreatic cancer (52–56), renal cell carcinoma (57), and lung cancer (58, 59). Esaki et al evaluated the synergistic effect between HF10 and GEM in a bilateral colorectal cancer model.…”