An Adenoviral Vaccine Encoding Full-Length Inactivated Human Her2 Exhibits Potent Immunogenicty and Enhanced Therapeutic Efficacy without Oncogenicity
- 28 February 2010
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 16 (5), 1466-1477
- https://doi.org/10.1158/1078-0432.ccr-09-2549
Abstract
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 imunogenic 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. Clin Cancer Res; 16(5); 1466–77Keywords
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This publication has 39 references indexed in Scilit:
- Therapeutic Vaccination Halts Disease Progression in BALB-neuT Mice: The Amplitude of Elicited Immune Response Is Predictive of Vaccine EfficacyHuman Gene Therapy, 2008
- Lapatinib Resistance in HCT116 Cells Is Mediated by Elevated MCL-1 Expression and Decreased BAK Activation and Not by ERBB Receptor Kinase MutationPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2008
- Therapy of Advanced Established Murine Breast Cancer with a Recombinant Adenoviral ErbB-2/neu VaccineCancer Research, 2008
- Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbB Ligands and Remain Dependent on the ErbB Receptor NetworkClinical Cancer Research, 2007
- The mouse mammary carcinoma 4T1: characterization of the cellular landscape of primary tumours and metastatic tumour fociInternational Journal of Experimental Pathology, 2007
- DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene listsNucleic Acids Research, 2007
- Targeting the function of the HER2 oncogene in human cancer therapeuticsOncogene, 2007
- Lapatinib Moves Forward in Inflammatory and Early HER2-Positive Breast Cancer TrialsJNCI Journal of the National Cancer Institute, 2007
- Adenovirus vaccination againstneu oncogene exerts long-term protection from tumorigenesis in BALB/neuT transgenic miceInternational Journal of Cancer, 2006
- DNA vaccination against neu reduces breast cancer incidence and metastasis in miceCancer Gene Therapy, 2001