FORPROTECT

BAVARIAN RESEARCH ASSOCIATION FOR INFECTION PROTECTION BY MEANS OF NEW DIAGNOSTIC AND THERAPEUTIC METHODS

T2 T2 - Therapy of solid tumors by adeno-associated virus

Research issues:
The tumor suppressor p53 is mutated in most the human tumors. The adeno-associated virus type 2 (AAV-2) is able to induce a temporary G2 cell cycle arrest. When the infected cell is p53 deficient, the AAV-2 infection leads to apoptosis. Since many of the human tumors contain a p53 mutation, wildtype AAV-2 posseses antitumor properties in vivo (Raj et al., 2001: Nature 412, 914-917). The combination of this very promising property of the wildtype with recombinant AAV-2 vectors, which codes for immunstimulatory proteins like CD40L and "secondary lymphoid-tissue chemokine", opens the possibility of a new treatment option for solid tumors like colon carcinomas. In this project we will investigate which mechanisms of AAV-2 are responsible for the induction of apoptosis in p53 deficient tumor cells and if it is possible to do a simultaneous gene transfer of immunostimulatory genes which results in a combinatory effect.

Application:
In this project we would like to work out a new concept for the therapy of solid tumors. In this approach the p53 deficient tumor cells should be directly killed by the proapoptotic ability of AAV-2 and in addition by the induction of an antitumor immunological answer mediated by the transfer of immunostimulatory molecules into the tumor cells. If possible, we would like to use cell specific or even better tumor specific AAV vectors for this approach, which would allow an efficient and safe systemic application. Since up to now no efficient method for the treatment of solid tumors like colon carcinomas is available, we assume that this project has a great commercial potential and a wide field of application.