Evaluation of twenty-one human adenovirus types and one infectivity-enhanced adenovirus for the treatment of malignant melanoma.
Advanced melanoma is associated with poor prognosis warranting the development of new therapeutics, such as oncolytic adenoviruses for immunovirotherapy. Since this approach critically depends on efficient transduction of targeted tumor cells, we screened a panel of 22 different adenovirus types for their internalization efficiency in melanoma cells. We demonstrated that the virions of Ad35, Ad38, and Ad3 have significantly higher internalization efficiency in melanoma cells than Ad5, so far the only adenovirus type used in clinical trials for melanoma. Therefore, we developed a conditionally replication-competent Ad5-based vector with the Ad35 fiber shaft and knob domains (Ad5/35) and compared its therapeutic efficacy with the homologous vector carrying the native Ad5 fiber. To further enhance virotherapy, we combined the oncolytic adenovirus vectors with intratumoral expression of measles virus fusogenic membrane glycoproteins H and F (MV-H/F) and dacarbazine chemotherapy. In a human melanoma xenograft model, established from a short-term culture of primary melanoma cells, we demonstrated that the Ad5/35-based therapy had a significantly greater anti-neoplastic effect than the homologous Ad5-based therapy. Furthermore, the combination of virotherapy, intratumoral expression of MV-H/F, and chemotherapy was clearly superior to single- or double-agent therapy. In conclusion, Ad35-based vectors are promising for the treatment of melanoma.
Hoffmann
Dennis
D
Department of Molecular and Medical Virology, Institute of Microbiology and Hygiene, Ruhr-University Bochum, Bochum, Germany.
Bayer
Wibke
W
Heim
Albert
A
Potthoff
Anja
A
Nettelbeck
Dirk M
DM
Wildner
Oliver
O
D000260:Adenoviruses, Human / Q000235:genetics / Q000502:physiology; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000627:therapeutic use; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000628:therapy*; D051916:Membrane Cofactor Protein / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy; D051603:Recoverin / Q000032:analysis; D012878:Skin Neoplasms / Q000188:drug therapy / Q000628:therapy*; D014760:Viral Fusion Proteins / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics; D053586:Virus Internalization; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D051916:Membrane Cofactor Protein; C496731:RCVRN protein, human; D014760:Viral Fusion Proteins; D014764:Viral Proteins; D051603:Recoverin; D003606:Dacarbazine