Harnessing Viruses to Treat Cancer, Developing Novel Gene-based Approaches

Cancer therapies, and therapies in general, are based on small molecules, radiation or surgery. To date, genes have not been used therapeutically. Gene and virus therapies have the potential to permanently change the genetic makeup of a given cell or tissue. In cancer, gene therapy can be used to permanently change a cancer cell's genetic composition to make it self-destruct. Alternatively, a cell or tissue can be taken out of the body, genetically altered, and re-introduced to the patient as a therapeutic agent by delivering the modified cells directly to the target site of interest in a patient. Removing cells, modifying them and putting them back in a person is much more complex than having a therapeutic agent in a bottle that you take off the shelf and administer to a patient.

The primary goals of the Gene and Virus Therapy Program are to:

• Enhance the understanding of the biology of viruses and cells that are used to develop novel gene transfer technologies
• Advance the technology base from which novel gene-based therapies are created
• Improve the outcome of cancer therapy by development and clinical testing of novel gene-based therapies

Controlled cell fusion

Mayo researchers are finding promising new ways to exploit a substance called fusogenic membrane glycoproteins (FMGs). They use FMGs in a process called controlled cell fusion to destroy cancer cells. They are destroyed directly by fusing them with other cancer cells, or indirectly by fusing the cancer cells with cells of the immune system, which creates a potent cancer vaccine. Mayo researchers are using this unique technology in clinical trials by engineering a measles virus that uses controlled cell fusion to kill cancer cells.

Vector/virus targeting

A virus has powerful potential in the body, because it invades cells and forces them to replicate the virus, which is how it spreads. Researchers are able to use this destructive power to kill cancer cells, but only if the virus is modified to target only the diseased cells. Similarly, vectors can reprogram the genes of cancer cells so that they die, but they are only effective if the vectors can get to the cancer cells. Major research in vector/virus targeting has been a cornerstone of the Mayo Clinic program. Vectors and viruses have to be engineered to first target specific cell types (gene delivery), then must also be targeted for gene expression (e.g., changing the genetic makeup of the cell) once gene delivery has taken place.

Cells as delivery devices

Even a vector that has been engineered to identify a particular type of target cell is very difficult to deliver directly to the target site after it is released into the bloodstream. The vector or virus often remains circulating in the bloodstream because it has no mechanism to get out into the tissue. Cells are better than viruses or nonviral vectors at changing their shape, escaping from blood vessels and migrating through tissues.

Therefore, Mayo researchers are studying various cell types and determining which are most effective at delivering the virus or vector to its target site (e.g., a cancerous tumor). T cells, macrophages, endothelial progenitor cells, smooth muscle progenitor cells, and other types of stem cells are being studied for this purpose.

Marker genes

After gene therapy treatment has taken place, it is vitally important that researchers discover whether a therapeutic gene is doing what it's supposed to do (e.g., kill cancer cells in a tumor). In the past, researchers have had to perform repeated and invasive biopsies on patients to monitor gene expression. Patients and researchers naturally prefer a noninvasive method, so Mayo researchers have developed a way to monitor the effectiveness of the treatment by doing a simple blood test or imaging investigation.

To achieve this, they introduce "marker genes" into gene therapy vectors before they are released into the bloodstream. These marker genes then show up in a blood test, or a CT or MRI scan, indicating whether or not the therapeutic gene is performing as expected. Knowing the results of the blood test or image then allows researchers to adjust and improve the gene therapy.

There are a large number of ongoing research projects underway in the Gene and Virus Therapy Program. Some of this research has led to advancements in the understanding of the science, laying the groundwork for additional hypotheses and further research.