PURPOSE: Metastatic gastric cancer remains a common and devastating disease without curative treatment. Recent proof-of-concept clinical trials have validated gene therapy with adenoviruses as an effective and safe modality for the treatment of cancer. However, expression of the primary coxsackie-adenovirus receptor is variable in advanced cancers, and therefore, the use of heterologous receptors could be advantageous. EXPERIMENTAL DESIGN: Here, we used capsid-modified adenoviruses for increasing the transduction and subsequent antitumor efficacy. 5/3 chimeric viruses have a serotype 3 knob which allows binding to a receptor distinct from coxsackie-adenovirus receptor. The fiber of Ad5lucRGD is modified with an integrin-targeted motif. Polylysine motifs, pK7 and pK21, bind to heparan sulfates. Oncolytic adenoviruses replicate in and kill tumor cells selectively. Gastric cancer cell lines and fresh clinical samples from patients were infected with transductionally targeted viruses. Capsid-modified oncolytic adenoviruses were used in cell killing experiments. To test viral transduction and therapeutic efficacy in vivo, we developed orthotopic mouse models featuring i.p. disseminated human gastric cancer, which allowed the evaluation of biodistribution and antitumor efficacy in a system similar to humans. RESULTS: Capsid modifications benefited gene transfer efficiency and cell killing in gastric cancer cell lines and clinical samples in vitro and in vivo. Modified oncolytic adenoviruses significantly increased the survival of mice with orthotopic gastric cancer. CONCLUSIONS: These preclinical data set the stage for the clinical evaluation of safety and efficacy in patients with disease refractory to current modalities.
PURPOSE: Metastatic gastric cancer remains a common and devastating disease without curative treatment. Recent proof-of-concept clinical trials have validated gene therapy with adenoviruses as an effective and safe modality for the treatment of cancer. However, expression of the primary coxsackie-adenovirus receptor is variable in advanced cancers, and therefore, the use of heterologous receptors could be advantageous. EXPERIMENTAL DESIGN: Here, we used capsid-modified adenoviruses for increasing the transduction and subsequent antitumor efficacy. 5/3 chimeric viruses have a serotype 3 knob which allows binding to a receptor distinct from coxsackie-adenovirus receptor. The fiber of Ad5lucRGD is modified with an integrin-targeted motif. Polylysine motifs, pK7 and pK21, bind to heparan sulfates. Oncolytic adenoviruses replicate in and kill tumor cells selectively. Gastric cancer cell lines and fresh clinical samples from patients were infected with transductionally targeted viruses. Capsid-modified oncolytic adenoviruses were used in cell killing experiments. To test viral transduction and therapeutic efficacy in vivo, we developed orthotopic mouse models featuring i.p. disseminated humangastric cancer, which allowed the evaluation of biodistribution and antitumor efficacy in a system similar to humans. RESULTS: Capsid modifications benefited gene transfer efficiency and cell killing in gastric cancer cell lines and clinical samples in vitro and in vivo. Modified oncolytic adenoviruses significantly increased the survival of mice with orthotopic gastric cancer. CONCLUSIONS: These preclinical data set the stage for the clinical evaluation of safety and efficacy in patients with disease refractory to current modalities.
Authors: Kenneth H Kim; Michael J Ryan; James E Estep; Brock M Miniard; Thomas L Rudge; James O Peggins; Trevor L Broadt; Minghui Wang; Meredith A Preuss; Gene P Siegal; Akseli Hemminki; Raymond D Harris; Rosemarie Aurigemma; David T Curiel; Ronald D Alvarez Journal: Hum Gene Ther Date: 2011-03-23 Impact factor: 5.695
Authors: Otto Hemminki; Iulia Diaconu; Vincenzo Cerullo; Saila K Pesonen; Anna Kanerva; Timo Joensuu; Kalevi Kairemo; Leena Laasonen; Kaarina Partanen; Lotta Kangasniemi; Andre Lieber; Sari Pesonen; Akseli Hemminki Journal: Mol Ther Date: 2012-08-07 Impact factor: 11.454
Authors: Anniina Koski; Lotta Kangasniemi; Sophie Escutenaire; Sari Pesonen; Vincenzo Cerullo; Iulia Diaconu; Petri Nokisalmi; Mari Raki; Maria Rajecki; Kilian Guse; Tuuli Ranki; Minna Oksanen; Sirkka-Liisa Holm; Elina Haavisto; Aila Karioja-Kallio; Leena Laasonen; Kaarina Partanen; Matteo Ugolini; Andreas Helminen; Eerika Karli; Päivi Hannuksela; Saila Pesonen; Timo Joensuu; Anna Kanerva; Akseli Hemminki Journal: Mol Ther Date: 2010-07-27 Impact factor: 11.454
Authors: Ilya V Ulasov; Matthew A Tyler; Angel A Rivera; Dirk M Nettlebeck; Joanne T Douglas; Maciej S Lesniak Journal: J Med Virol Date: 2008-09 Impact factor: 2.327
Authors: Raquel Yokoda; Bolni M Nagalo; Mansi Arora; Jan B Egan; James M Bogenberger; Thomas T DeLeon; Yumei Zhou; Daniel H Ahn; Mitesh J Borad Journal: Oncolytic Virother Date: 2018-03-23