title: Neoadjuvant in situ gene-mediated cytotoxic immunotherapy improves postoperative outcomes in novel syngeneic esophageal carcinoma models.
abstract: Esophageal carcinoma is the most rapidly increasing tumor in the United States and has a dismal 15% 5-year survival. Immunotherapy has been proposed to improve patient outcomes; however, no immunocompetent esophageal carcinoma model exists to date to test this approach. We developed two mouse models of esophageal cancer by inoculating immunocompetent mice with syngeneic esophageal cell lines transformed by cyclin-D1 or mutant HRAS(G12V) and loss of p53. Similar to humans, surgery and adjuvant chemotherapy (cisplatin and 5-fluorouracil) demonstrated limited efficacy. Gene-mediated cyototoxic immunotherapy (adenoviral vector carrying the herpes simplex virus thymidine kinase gene in combination with the prodrug ganciclovir; AdV-tk/GCV) demonstrated high levels of in vitro transduction and efficacy. Using in vivo syngeneic esophageal carcinoma models, combining surgery, chemotherapy and AdV-tk/GCV improved survival (P=0.007) and decreased disease recurrence (P<0.001). Mechanistic studies suggested that AdV-tk/GCV mediated a direct cytotoxic effect and an increased intra-tumoral trafficking of CD8 T cells (8.15% vs 14.89%, P=0.02). These data provide the first preclinical evidence that augmenting standard of care with immunotherapy may improve outcomes in the management of esophageal carcinoma.
authors.affiliation: Department of Surgery, Division of Thoracic Surgery, Hospital of the University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Predina
authors.forename: B
authors.initials: B
authors.lastname: Judy
authors.forename: L A
authors.initials: LA
authors.lastname: Aliperti
authors.forename: Z G
authors.initials: ZG
authors.lastname: Fridlender
authors.forename: A
authors.initials: A
authors.lastname: Blouin
authors.forename: V
authors.initials: V
authors.lastname: Kapoor
authors.forename: B
authors.initials: B
authors.lastname: Laguna
authors.forename: H
authors.initials: H
authors.lastname: Nakagawa
authors.forename: A K
authors.initials: AK
authors.lastname: Rustgi
authors.forename: L
authors.initials: L
authors.lastname: Aguilar
authors.forename: E
authors.initials: E
authors.lastname: Aguilar-Cordova
authors.forename: S M
authors.initials: SM
authors.lastname: Albelda
authors.forename: S
authors.initials: S
authors.lastname: Singhal
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019938:Cyclin D1 / Q000235:genetics; D003602:Cytotoxicity, Immunologic; D004938:Esophageal Neoplasms / Q000628:therapy*; D005260:Female; D011905:Genes, ras / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D020360:Neoadjuvant Therapy / Q000379:methods*; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D009374:Neoplasms, Experimental / Q000628:therapy*; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C530105:Ccnd1 protein, mouse; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D013937:Thymidine Kinase