Infectivity-enhanced adenoviruses deliver efficacy in clinical samples and orthotopic models of disseminated gastric cancer.
OBJECTIVE
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.


METHODS
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.
Kangasniemi
Lotta
L
Rational Drug Design Program, University of Helsinki, Finland.
Kiviluoto
Tuula
T
Kanerva
Anna
A
Raki
Mari
M
Ranki
Tuuli
T
Sarkioja
Merja
M
Wu
Hongju
H
Marini
Frank
F
Höckerstedt
Krister
K
Isoniemi
Helena
H
Alfthan
Henrik
H
Stenman
Ulf-Håkan
UH
Curiel
David T
DT
Hemminki
Akseli
A
D000256:Adenoviridae / Q000472:pathogenicity*; D000818:Animals; D002213:Capsid / Q000378:metabolism*; D016923:Cell Death; D002470:Cell Survival; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D051379:Mice; D009374:Neoplasms, Experimental; D050130:Oncolytic Virotherapy; D011991:Receptors, Virus; D013274:Stomach Neoplasms / Q000473:pathology / Q000628:therapy*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus