Abstract
Monoclonal anti-HER2 antibody trastuzumab has significantly improved the survival of patients with HER2-overexpressing tumors. Nevertheless, systemic antibody therapy is expensive, limited in efficacy due to physical tumor barriers, and carries the risk of severe side effects such as cardiomyopathy. Oncolytic viruses mediate cancer-selective transgene expression, kill infected cancer cells while mounting antitumor immune responses, and have recently demonstrated promising efficacy in combination treatments. Here, we armed an oncolytic adenovirus with full-length trastuzumab to achieve effective in situ antibody production coupled with progressive oncolytic cancer cell killing. We constructed an infectivity-enhanced serotype 5 oncolytic adenovirus, Ad5/3-Δ24-tras, coding for human trastuzumab antibody heavy- and light-chain genes, connected by an internal ribosome entry site. Infected cancer cells were able to assemble full-length functional antibody, as confirmed by Western blot, ELISA, and antibody-dependent cell-mediated cytotoxicity assay. Importantly, oncolysis was required for release of the antibody into tumors, providing additional spatial selectivity. Ad5/3-Δ24-tras showed potent in vitro cytotoxicity and enhanced antitumor efficacy over oncolytic control virus Ad5/3-Δ24 or commercial trastuzumab in HER2-positive cancer models in vivo (both P < 0.05). Furthermore, Ad5/3-Δ24-tras resulted in significantly higher tumor-to-systemic antibody concentrations (P < 0.001) over conventional delivery. Immunological analyses revealed dendritic cell activation and natural killer cell accumulation in tumor-draining lymph nodes. Thus, Ad5/3-Δ24-tras is an attractive anticancer approach combining oncolytic immunotherapy with local trastuzumab production, resulting in improved in vivo efficacy and immune cell activation in HER2-positive cancer. Moreover, the finding that tumor cells can produce functional antibody as directed by oncolytic virus could lead to many valuable antitumor approaches. Mol Cancer Ther; 15(9); 2259-69. ©2016 AACR.
Highlights
HER2 is a key tumor-associated molecule, providing growth signal and contributing to resistance to standard hormonal and chemotherapies, associating with poor prognosis [1,2,3]
We constructed an oncolytic adenovirus Ad5/3-D24-tras, and two nonreplicating control viruses Ad5/3-tras and Ad5-tras, each coding for trastuzumab heavy- and light-chain genes linked together by an internal ribosome entry site (IRES) sequence [28], which allows for translation of both mRNAs without the need for additional promoters
Monoclonal anti-HER2 antibody therapy with trastuzumab has significantly improved the survival of HER2-expressing breast and, more recently, of gastric cancer patients [2, 5]
Summary
HER2 is a key tumor-associated molecule, providing growth signal and contributing to resistance to standard hormonal and chemotherapies, associating with poor prognosis [1,2,3]. Routine examination of tumor HER2 status and systemic therapy with anti-HER2 antibody trastuzumab have become standard oncology practice for. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). HER2-positive cancers, owing to the significant survival benefits seen [2, 5]. Trastuzumab is a high-affinity humanized antibody targeting the extracellular domain of HER2-mediating several antitumor activities. IgG class antibody possessing a human Fc region, such as trastuzumab, can prime target cells for attack by the immune system [7, 8]
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