Targeting oncolytic viruses to colorectal tumors

Cancers of the colon and rectum remain responsible for 56,000 deaths every year in the US, second only to lung cancer. Early detection of the disease is particularly important and in the US alone, around 140,000 new cases of colorectal cancer were estimated to have been detected in 2002. This makes colorectal cancer the third most common cancer in the US. Surgery remains the main form of treatment and is often the only treatment used in early-stage disease. Current surgical practices can however cure only 40%-50% of early-stage cases. The global colorectal cancer market was estimated to be worth approximately US$1 billion in 2001, of which 60% of the revenues were derived from the US. The market has been predicted to rise further to US$2.5-3 billion within a five-year period. Camptosar™ (Pharmacia Corp.) currently dominates the US colorectal cancer market, but severe diarrhea as a side effect is a clear drawback for this drug (for a full analysis of therapeutic and market opportunities for colon cancer click here).

Oncolytic viruses represent an emerging approach to the treatment of cancer. Although the cytotoxic effects of viruses are usually viewed in terms of pathogenicity, it is possible to harness this activity for therapeutic purposes. In particular, viral genomes are highly versatile, and can be modified to direct their cytotoxicity towards cancer cells. To our knowledge there are almost 20 such oncolytic virus-based therapeutics in development by the pharma/biotech sector. Although most of these are in preclinical development, therapies from Cell Genesys, Crusade, Medigene and Oncolytics are more advanced.

The use of replication-competent gene therapy viruses, which have a cytolytic cycle, has emerged as a viable strategy to specifically kill tumor cells. The development of this approach depends however on the ability to effectively target viral replication to tumor cells. In a recent Molecular Cancer Therapeutics paper researchers from Cell Genesys have taken advantage of the selective over-expression the carcioembryonic antigen (CEA) in colorectal cancer to design an oncolytic virus that is tumor selective.

CEA is a cell surface glycoprotein normally expressed in fetal tissue and transcriptionally silent in adults. It is a member of the immunoglobulin supergene family found on chromosome 19. CEA functions as an intercellular adhesion molecule and plays an important role during development. However, CEA overexpression is associated with a variety of cancers of epithelial origin. Serum CEA elevation is observed in over 60% of patients with metastatic colorectal cancer. Expression of CEA in epithelial tumors occurs at the level of gene transcription and essential transcriptional regulatory elements of the CEA gene can therefore be exploited therapeutically by inserting them into viral vectors. Previous studies have demonstrated that incorporating these elements into viral vectors in such a way that they drive the expression of suicide genes can confer target specificity.

Cell Genesys have now used a similar approach to engineer a replication-competent oncolytic virus in which the CEA transcriptional regulatory elements were exploited to drive the expression of the viral E1A gene that is essential for replication. In particular a construct consisting of the enhancer 1 region and the promoter of CEA drove high levels of gene expression in a luciferase gene expression assay. A recombinant adenoviruses was then constructed in which the native E1A gene region was replaced by the CEA enhancer 1/promoter region. This resulted in an approximate 1000-fold selectivity for viral replication in CEA positive compared to CEA negative cancer cells. In vivo efficacy was observed for this engineered virus. In mice xenografted with the CEA positive human colon cancer LoVo cell lines, the engineered virus was able to dramatically prevent tumor growth. Indeed while tumor size increased 10-fold over the 4 week study period in untreated mice, tumor size in those treated with the engineered virus remained largely unchanged with no adverse effects being observed.

These exciting data open new paths for the development of oncolytic viruses and the future optimization of such an approach by the development of viruses that selectively replicate in cancer cell and which are also able to transfect the cells with therapeutic genes represents a further area for optimization.

Entry date Tuesday, December 16, 2003

Adapted from Li et al, Mol Cancer Ther. 2003 Oct;2(10):1003-9.