Publications [#178160] of Gayathri R Devi

Papers Published

1. ZC Hartman, J Wei, T Osada, O Glass, G Lei, XY Yang, S Peplinski, DW Kim, W Xia, N Spector, J Marks, W Barry, A Hobeika, G Devi, A Amalfitano, MA Morse, HK Lyerly, TM Clay, An adenoviral vaccine encoding full-length inactivated human Her2 exhibits potent immunogenicty and enhanced therapeutic efficacy without oncogenicity., Clinical cancer research : an official journal of the American Association for Cancer Research, vol. 16 no. 5 (March, 2010), pp. 1466-77, ISSN 1078-0432 [doi]
   (last updated on 2013/05/16)

   Abstract:
   OBJECTIVE: 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. METHODS: 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.

   Keywords:
   Adenoviridae • Animals • Blotting, Western • Cancer Vaccines • Cell Separation • Female • Flow Cytometry • Genes, erbB-2 • Genetic Therapy • Genetic Vectors • Humans • Mammary Neoplasms, Experimental • Mice • Mice, Transgenic • Oligonucleotide Array Sequence Analysis • Receptor, erbB-2 • Reverse Transcriptase Polymerase Chain Reaction • Vaccination • genetics • immunology • immunology* • metabolism • methods • methods* • therapeutic use* • therapy*