|Title / Titel||Generation and charecterization of improved variants of oncolytic, melanoma-specific adenoviruses|
|Abstract (PDF, 14 KB)|
|Summary / Zusammenfassung||We have developed an attenuated, replication-competent adenovirus (Ad) specific for melanoma (Ad∆EP-TETP) and demonstrated the selective oncolytic activity of this virus using xenotransplanted melanomas (Peter et al., Gene Therapy (2003) 10: 530-539). In this system, selective replication of Ad is achieved due to tissue-specific expression control of E1A, the main viral switch controlling gene expression and replication. In the meantime we have constructed two additionally modified genetic variants of this virus, one carrying the E1A six amino acid deletion (Ad∆EP-TETP-∆E1A 122-129), and the second carrying the E1B-19 kDa deletion (Ad∆EP-TETP-∆E1B19 kDa). In addition, a combined virus (Ad∆EP-TETP-∆E1A 122-129-∆E1B-19 kDa) was produced. The E1A modification should attenuate this virus in cell cycle-deregulated cells such as Rb- or cyclin-mutated tumor cells, whereas the deletion of the anti-apoptotic E1B-19 kDa gene should lead to a more potent cytolytic virus. In order to further increase the efficacy of the melanoma-specific oncolytic virus it is planed to introduce a fiber of a different Ad serotype (Ad35) with a much broader tropism in place of the endogenous fiber. This should allow to infect cells that do not express the receptor for the commonly used Ad-5-based vectors.|
|Publications / Publikationen||A novel attenuated replication-competent adenovirus for melanoma therapy
Peter, I., Graf C., Dummer, R., Schaffner, W., Greber, U. F., Hemmi, S.
Gene Ther 10: 530-9 (2003)The avb5 integrin of hematopoietic and non-hematopoietic cells is a transduction receptor of RGD-4C fiber-modified adenoviruses
Nagel, H., Maag, S., Tassis, A., Nestlé, F. O., Greber, U. F. and Hemmi, S.
Gene Ther 10: 1643-53 (2003)Melanoma cultures show different susceptibility towards E1A-, E1B-19 kDa- and fiber-modified replication-competent Adenoviruses
Schmitz, M., Graf, C., Gut, T., Sirena,D., Peter, I., Dummer, R., Greber, U.F., and Hemmi, S.
Gene Therapy 13: 893-905 (2006)
|Keywords / Suchbegriffe||adenovirus, oncolytic virus, virus tropism, melanoma|
|Project leadership and contacts /
Projektleitung und Kontakte
|Funding source(s) /
Krebsliga Kanton Zürich
|Duration of Project / Projektdauer||Jun 2003 to Dec 2004|