ADENOVIRUS REPLICATION-COMPETENT ANTI-CANCER VECTOR

DESCRIPTION (provided by applicant): We have developed several tumor-specific and tissue-specific replication-competent adenoviruses (Ad) vectors for cancer gene therapy. One vector, named KD3, has a mutation in the E1A gene such that KD3 cannot replicate in, and destroy, "normal" cells. However, KD3 can replicate in cancer cells because they have a microenvironment conducive to KD3 replication. KD3 is efficient in lysing cells and spreading from cell-to-cell, because it overexpresses a protein named ADP which enhances cell lysis. A second vector, named GZ3, is identical to KD3 except it has a wild-type E1A gene. GZ3 is very cytolytic, but it is not tumor-specific and could not be used in its present form to treat cancer. In the past year, we have continued in our attempt to develop optimal vectors to treat cancer. We have constructed new vectors, named KD3-COL and GZ3-COL, where the E4 promoter is replaced by a colon cancer-specific promoter named COL. These Ad vectors replicate in colon cancer cells but not other types of cells. We have also constructed vectors named KD3-TERT and GZ3-TERT, which have the E4 promoter replaced by the TERT promoter for telomerase. These vectors should replicate in telomerase-positive cancer cells but not in normal cells. We have also constructed a version of KD3 that secretes an apoptosis-inducing protein without precluding the replication of the vector. This vector should destroy tumors by two mechanisms, vector lytic replication and apoptosis of uninfected cells surrounding the infected cells. Hopefully, the secreted protein may be able to induce apoptosis in tumors that have metastasized. We propose to characterize KD3-COL, GZ3-COL, KD3-TERT, GZ3-TERT, and the apoptosis-inducing vector in cell culture, with the primary aim of ascertaining their specificity to cancer cells together with their ability to replicate and spread in these cells. They will also be evaluated for their ability to destroy or suppress the growth of human cancer cells in immunodeficient nude mice. These tumors will be examined with respect to their growth, pathology, and ability to support vector replication. The toxicity and distribution of these vectors in mice will be studied.

PROPOSED COMMERCIAL APPLICATION: Cancer is the second leading cause of death in the USA. The adenovirus anti-cancer vectors that wwe have developed are expected to provide effective treatment of many different types of cancers, including colon and prostate. Accordingly, the market potential is extremely large.