acyclovir and Pancreatic-Neoplasms

While surgical resection of pancreatic adenocarcinoma provides the only chance of cure, long-term survival remains poor. Immunotherapy may improve outcomes, especially as adjuvant to local therapies. Gene-mediated cytotoxic immunotherapy (GMCI) generates a systemic anti-tumor response through local delivery of an adenoviral vector expressing the HSV-tk gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug. GMCI has demonstrated synergy with standard of care (SOC) in other tumor types. This is the first application in pancreatic cancer.. Four dose levels (3 × 10(10) to 1 × 10(12) vector particles) were evaluated as adjuvant to surgery for resectable disease (Arm A) or to 5-FU chemoradiation for locally advanced disease (Arm B). Each patient received two cycles of AdV-tk + prodrug.. Twenty-four patients completed therapy, 12 per arm, with no dose-limiting toxicities. All Arm A patients were explored, eight were resected, one was locally advanced and three had distant metastases. CD8(+) T cell infiltration increased an average of 22-fold (range sixfold to 75-fold) compared with baseline (p = 0.0021). PD-L1 expression increased in 5/7 samples analyzed. One node-positive resected patient is alive >66 months without recurrence. Arm B RECIST response rate was 25 % with a median OS of 12 months and 1-year survival of 50 %. Patient-reported quality of life showed no evidence of deterioration.. AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer.

Topics: Acyclovir; Adenocarcinoma; Adenoviridae; Adult; Aged; Chemoradiotherapy; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Genetic Therapy; Genetic Vectors; Humans; Immunohistochemistry; Immunotherapy; Male; Middle Aged; Neoplasm Recurrence, Local; Pancreatic Neoplasms; Thymidine Kinase; Valacyclovir; Valine

A 76-year-old woman was admitted to our hospital due to diabetes and was diagnosed with advanced pancreatic cancer for which she received gemcitabine plus nab-paclitaxel. Fourteen days later, eruptions were observed in the first division of the right trigeminal nerve;she was then diagnosed with herpes zoster and was successfully treated with antiviral therapy. Seven days after the herpes zoster infection, right ophthalmoplegia appeared. Oculomotor nerve palsy secondary to herpes zoster ophthalmicus was suspected and she was treated with steroid pulse therapy. Her symptoms improved, and chemotherapy was able to be continued. Her ophthalmoplegia had almost fully resolved 41 days after the onset of herpes zoster infection.

Topics: Acyclovir; Aged; Albumins; Antiviral Agents; Deoxycytidine; Female; Gemcitabine; Humans; Oculomotor Nerve Diseases; Paclitaxel; Pancreatic Neoplasms

A recombinant retroviral vector pNTK expressing the "suicide" gene herpes simplex virus thymidine kinase (HSV-TK) gene was constructed. The recombinant vector was packaged by PA317 cells and viral supernatant was used to infect the human pancreatic carcinoma cell line PC-2. After selection in G418, resistant colonies were identified and isolated. Cytotoxic effects of the non-toxic prodrug Acyclovir (ACV) or Ganciclovir (GCV) to the NTK transformant PC-2 cells was more than 90%, while that of the control PC-2 cells was less that 10%. Furthermore, the "bystander effect" of HSV-TK on PC-2 cells was also observed.

Topics: Acyclovir; Antiviral Agents; DNA, Recombinant; Ganciclovir; Humans; Pancreatic Neoplasms; Plasmids; Retroviridae; Simplexvirus; Thymidine Kinase; Transfection; Tumor Cells, Cultured