Neoadjuvant in situ gene-mediated cytotoxic immunotherapy improves postoperative outcomes in novel syngeneic esophageal carcinoma models

J. D. Predina, B. Judy, L. A. Aliperti, Z. G. Fridlender, A. Blouin, V. Kapoor, B. Laguna, H. Nakagawa, A. K. Rustgi, L. Aguilar, E. Aguilar-Cordova, S. M. Albelda, S. Singhal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

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.

Original languageAmerican English
Pages (from-to)871-883
Number of pages13
JournalCancer Gene Therapy
Volume18
Issue number12
DOIs
StatePublished - Dec 2011
Externally publishedYes

Bibliographical note

Funding Information:
JDP was supported by a grant from the American Medical Association Foundation, LA was supported from the Lavin Family Supporting Foundation, SS was supported by the National Institutes of Health (K12CA076931 and Pilot award from the Center for Molecular Studies in Digestive and Liver Diseases P30-DK050306), and HN and AKR were supported by NCI P01-CA098101 (Mechanisms of Esophageal Carcinogenesis).

Keywords

  • animal models
  • esophageal carcinoma
  • immunotherapy
  • neoadjuvant therapy
  • surgery

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