An adenoviral vaccine encoding full-length inactivated human Her2 exhibits potent immunogenicty and enhanced therapeutic efficacy without oncogenicity.

Published

Journal Article

PURPOSE: Overexpression of the breast cancer oncogene HER2 correlates with poor survival. Current HER2-directed therapies confer limited clinical benefits and most patients experience progressive disease. Because refractory tumors remain strongly HER2+, vaccine approaches targeting HER2 have therapeutic potential, but wild type (wt) HER2 cannot safely be delivered in immunogenic viral vectors because it is a potent oncogene. We designed and tested several HER2 vaccines devoid of oncogenic activity to develop a safe vaccine for clinical use. EXPERIMENTAL DESIGN: We created recombinant adenoviral vectors expressing the extracellular domain of HER2 (Ad-HER2-ECD), ECD plus the transmembrane domain (Ad-HER2-ECD-TM), and full-length HER2 inactivated for kinase function (Ad-HER2-ki), and determined their immunogenicity and antitumor effect in wild type (WT) and HER2-tolerant mice. To assess their safety, we compared their effect on the cellular transcriptome, cell proliferation, anchorage-dependent growth, and transformation potential in vivo. RESULTS: Ad-HER2-ki was the most immunogenic vector in WT animals, retained immunogenicity in HER2-transgenic tolerant animals, and showed strong therapeutic efficacy in treatment models. Despite being highly expressed, HER2-ki protein was not phosphorylated and did not produce an oncogenic gene signature in primary human cells. Moreover, in contrast to HER2-wt, cells overexpressing HER2-ki were less proliferative, displayed less anchorage-independent growth, and were not transformed in vivo. CONCLUSIONS: Vaccination with mutationally inactivated, nononcogenic Ad-HER2-ki results in robust polyclonal immune responses to HER2 in tolerant models, which translates into strong and effective antitumor responses in vivo. Ad-HER2-ki is thus a safe and promising vaccine for evaluation in clinical trials.

Full Text

Duke Authors

Cited Authors

  • Hartman, ZC; Wei, J; Osada, T; Glass, O; Lei, G; Yang, X-Y; Peplinski, S; Kim, D-W; Xia, W; Spector, N; Marks, J; Barry, W; Hobeika, A; Devi, G; Amalfitano, A; Morse, MA; Lyerly, HK; Clay, TM

Published Date

  • March 1, 2010

Published In

Volume / Issue

  • 16 / 5

Start / End Page

  • 1466 - 1477

PubMed ID

  • 20179231

Pubmed Central ID

  • 20179231

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-09-2549

Language

  • eng

Conference Location

  • United States