Enhanced antitumor efficacy of fiber-modified, midkine promoter-regulated oncolytic adenovirus in human malignant mesothelioma

Our plain-English summary of Enhanced antitumor efficacy of fiber-modified, midkine promoter-regulated oncolytic adenovirus in human malignant mesothelioma, by M. Takagi-Kimura, T. Yamano, A. Tamamoto, et al (Cancer Science, 2013).

The study

• Authors: M. Takagi-Kimura, T. Yamano, A. Tamamoto, N. Okamura, H. Okamura, T. Hashimoto-Tamaoki, M. Tagawa, N. Kasahara, S. Kubo
• Journal: Cancer Science
• Published: 2013;104(11):1433-9
• Cited by: 23 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Oncolytic virotherapy using adenoviruses has potential for therapeutic benefits in malignant mesothelioma. However, the downregulation of coxsackie virus/adenovirus receptor (CAR) expression is frequently a critical rate-limiting factor that impedes the effectiveness of adenovirus serotype 5 (Ad5)-based vectors in many cancer types. We evaluated CAR (Ad5 receptor) and CD46 (adenovirus serotype 35 [Ad35] receptor) expression in six human malignant mesothelioma cell lines. Very low CAR expression was observed in MSTO-211H and NCI-H2052 cells, whereas the other cell lines showed strong expression. In contrast, CD46 was highly expressed in all mesothelioma cell lines. On this basis, we replaced the CAR binding sequence of Ad5 with the CD46 binding sequence of Ad35 in the replication-defective adenoviruses and the tumor-specific midkine promoter-regulated oncolytic adenoviruses. By this fiber modification, the infectivity, virus progeny production, and in vitro cytocidal effects of the adenoviruses were significantly enhanced in low CAR-expressing MSTO-211H and NCI-H2052 cells, also resulting in similar or even higher levels in high CAR-expressing mesothelioma cell lines. In MSTO-211H xenograft models, the fiber-modified oncolytic adenovirus significantly enhanced antitumor effect compared to its equivalent Ad5-based vector. Our data demonstrate that Ad35 fiber modification of binding tropism in a midkine promoter-regulated oncolytic Ad5 vector confers transductional targeting to oncolytic adenoviruses, thereby facilitating more effective treatment of malignant mesothelioma.

© 2013 Japanese Cancer Association.

In plain English

This was a laboratory study in human cell lines and in mice, testing oncolytic (tumour-killing) adenoviruses against malignant mesothelioma, a cancer the authors note is often caused by exposure to asbestos. Using flow cytometry, the authors measured two cell-surface receptors, CAR (used by adenovirus serotype 5, Ad5) and CD46 (used by serotype 35, Ad35), in an immortalised mesothelial line and six mesothelioma cell lines. CAR was very low in MSTO-211H and NCI-H2052, while CD46 was high in all six. They then built four vectors: two replication-defective controls with either the Ad5 fibre (Ad843) or an Ad5/F35-modified, CD46-binding fibre (Ad844), and two oncolytic viruses whose E1 gene was driven by the midkine (MDK) promoter, again with the Ad5 fibre (Ad888) or the modified fibre (Ad889). Fibre modification increased infection, viral progeny production and cell killing in the CAR-low lines, while Ad889 caused no apparent killing of normal mesothelial cells, Met5A or fibroblasts at the highest dose tested. In mice bearing MSTO-211H tumours, the fibre-modified oncolytic virus reduced tumour volume further than the Ad5 version. The authors concluded that Ad35 fibre modification of MDK-regulated oncolytic Ad5 vectors enhances antitumour efficacy, especially where CAR is downregulated.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experimental study: in vitro work in human cell lines plus a subcutaneous xenograft experiment in nude mice
• Who was studied: Six human malignant mesothelioma cell lines (ACC-MESO-1, ACC-MESO-4, MSTO-211H, NCI-H2052, NCI-H2452, NCI-H28), plus normal mesothelial cells, immortalised Met5A cells and fibroblasts; and female nude mice bearing subcutaneous MSTO-211H tumours (11 per treatment group)
• Exposure: Not a human exposure study; cells and tumours were treated with adenoviral vectors: replication-defective Ad843 (Ad5 fibre) and Ad844 (Ad5/F35 fibre), and midkine promoter-regulated oncolytic Ad888 (Ad5 fibre) and Ad889 (Ad5/F35 fibre)
• Main results:
  • CAR expression was very low in MSTO-211H and NCI-H2052 cells and higher in the other lines tested
  • CD46 was highly expressed in all the mesothelioma cell lines
  • Infectivity of the fibre-modified replication-defective virus (Ad844) versus Ad843 was increased 6.53-fold in MSTO-211H and 23.08-fold in NCI-H2052 (normalised to normal mesothelial cells)
  • Virus progeny production by fibre-modified oncolytic Ad889 versus Ad888 was higher in the low CAR-expressing lines: 3.7-fold in MSTO-211H and 9.1-fold in NCI-H2052
  • In the CAR-low lines, Ad889 killed cells at a 10-fold lower dose than Ad888 (MOI of 1 versus 10)
  • The replication-defective vectors Ad843 and Ad844 caused no apparent cell death up to an MOI of 1000 in any cell line tested
  • Oncolytic Ad889 caused no apparent death of normal mesothelial cells, Met5A or fibroblasts even at an MOI of 1000
  • In MSTO-211H xenografts at day 49, mean tumour volume was 1159.2 (SD 321.7) cubic millimetres with Ad888, 1958.5 (SD 437.5) with PBS and 2066.3 (SD 475.6) with Ad844, a 40.8 to 43.9% reduction for Ad888
  • Fibre-modified Ad889 gave mean tumour volume 466.3 (SD 175.6) cubic millimetres at day 49, a 59.8% reduction compared with Ad888 (P less than 0.05)
• The authors' conclusion: The authors concluded that Ad35 fibre modification of midkine promoter-targeted oncolytic adenovirus vectors increased viral infectivity and gave enhanced transduction efficiency and antitumour efficacy in mesothelioma cells, particularly those with downregulated CAR, and that such dual-targeted vectors may be a promising strategy
• Limitations the authors state:
  • The in vivo test of the fibre-modified virus in CAR-low cells could only be done in MSTO-211H tumours, because NCI-H2052 cells do not form tumours in nude mice
  • Low CAR expression did not fully predict response, as the unmodified Ad888 also killed MSTO-211H cells extensively; the authors state CAR deficiency can be outweighed by other factors
  • The authors note that in clinical settings CAR/CD46 and MDK expression in tumour specimens would need to be evaluated to select a suitable vector

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Mesothelioma.

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