title: Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Advantagene, Inc., Auburndale, MA, 02466, USA.
authors: Laura K
authors: LK
authors: Aguilar
authors: Lawrence A
authors: LA
authors: Shirley
authors: Vincent M
authors: VM
authors: Chung
authors: Christopher L
authors: CL
authors: Marsh
authors: Jon
authors: J
authors: Walker
authors: Walter
authors: W
authors: Coyle
authors: Howard
authors: H
authors: Marx
authors: Tanios
authors: T
authors: Bekaii-Saab
authors: Gregory B
authors: GB
authors: Lesinski
authors: Benjamin
authors: B
authors: Swanson
authors: Daniel
authors: D
authors: Sanchez
authors: Andrea G
authors: AG
authors: Manzanera
authors: Estuardo
authors: E
authors: Aguilar-Cordova
authors: Mark
authors: M
authors: Bloomston
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000328:Adult; D000368:Aged; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D013937:Thymidine Kinase / Q000235:genetics; D000077483:Valacyclovir; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D013937:Thymidine Kinase; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir