Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses.
Renal cancer is a common and deadly disease that lacks curative treatments when metastatic. Here, we have used oncolytic adenoviruses, a promising developmental approach whose safety has recently been validated in clinical trials. Although preliminary clinical efficacy data exist for selected tumor types, potency has generally been less than impressive. One important reason may be that expression of the primary receptor, coxsackie-adenovirus receptor, is often low on many or most advanced tumors, although not evaluated in detail with renal cancer. Here, we tested if fluorescence-assisted cell sorting could be used to predict efficacy of a panel of infectivity-enhanced capsid-modified marker gene expressing adenoviruses in renal cancer cell lines, clinical specimens, and subcutaneous and orthotopic murine models of peritoneally metastatic renal cell cancer. The respective selectively oncolytic adenoviruses were tested for killing of tumor cells in these models, and biodistribution after locoregional delivery was evaluated. In vivo replication was analyzed with noninvasive imaging. Ad5/3-Delta24, Ad5-Delta24RGD, and Ad5.pK7-Delta24 significantly increased survival of mice compared with mock or wild-type virus and 50% of Ad5/3-Delta24 treated mice were alive at 320 days. Because renal tumors are often highly vascularized, we investigated if results could be further improved by adding bevacizumab, a humanized antivascular endothelial growth factor antibody. The combination was well tolerated but did not improve survival, suggesting that the agents may be best used in sequence instead of together. These results set the stage for clinical testing of oncolytic adenoviruses for treatment of metastatic renal cancer currently lacking other treatment options.
Guse
Kilian
K
Cancer Gene Therapy Group, University of Helsinki, Finland.
Ranki
Tuuli
T
Ala-Opas
Martti
M
Bono
Petri
P
Särkioja
Merja
M
Rajecki
Maria
M
Kanerva
Anna
A
Hakkarainen
Tanja
T
Hemminki
Akseli
A
D000256:Adenoviridae / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab; D002213:Capsid / Q000737:chemistry / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000556:secondary / Q000628:therapy*; D003131:Combined Modality Therapy; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D050130:Oncolytic Virotherapy; D010534:Peritoneal Neoplasms / Q000556:secondary / Q000628:therapy*; D011991:Receptors, Virus / Q000378:metabolism; D019076:Transgenes / Q000502:physiology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D019812:Heparan Sulfate Proteoglycans; D011991:Receptors, Virus; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D008156:Luciferases