If it worked in Troy, then why not with cancer?
BY MITZI BAKER
Another seemingly impenetrable wall has succumbed to the Trojan horse strategy. This time, instead of the ramparts of Troy and a wooden steed filled with soldiers, it's the wall of the blood vessel that is breached by an immune cell carrying tumor-killing viral particles.
This combination of two proven anti-tumor therapies—immune cells and a modified virus—resulted in a highly effective method for eliminating cancers in mice, according to findings from researchers at the School of Medicine, published in the March 24 issue of Science. While each strategy is somewhat successful on its own, merging the two had even more powerful results.
"We thought that the strengths of each approach would be complementary, but it works even better than we anticipated," said Christopher Contag, PhD, the senior author of the article and associate professor of microbiology and immunology and of pediatrics. In one set of results, the researchers found that the method resulted in complete recovery for an entire group of mice with ovarian tumors. In a second group of mice with breast tumors, there was a 75 percent rate of complete recovery.
The paper's first author, Steve Thorne, PhD, is a research associate in Contag's lab. He has a background in virology and was interested in how to make tumor-killing viruses, called oncolytic viruses, more effective. Thorne was looking for some kind of coating that would escort the virus to the tumor.
Contag and the paper's third author, Robert Negrin, MD, suggested putting the virus inside a cell. The two scientists had previously shown that a type of cell known as cytokine-induced killer cells, or CIK cells, can migrate to tumors in the body. They thought these cells might be an ideal way to deliver the virus to the tumor.
CIK cells have been studied for years by Negrin, professor of medicine and director of the Blood and Marrow Transplant Program at Stanford. Working with Contag, he has demonstrated that they seek and destroy tumor cells in mice, and he has been testing them in clinical trials for cancer patients. If the CIK cells had some additional weaponry, the Stanford team thought they might be able to deliver a more deadly payload.
A modified vaccinia virus (similar to the type used in the smallpox vaccine) appeared to be a plausible candidate; it destroys a tumor very quickly, but has been modified to make it very selective for tumor cells and not for normal cells.
The researchers first ensured that putting the virus into the CIK cells didn't affect its ability to seek out and attack tumors. One of the most striking results of this study was that the modified virus could lie dormant in the CIK cells for the length of time that it takes the cells to find the tumor. The cells move from the blood across the blood vessel wall and then, just like the Trojan horse, the virus is released in the tumor.
To be able to see the CIK/virus delivery to tumor cells in action, the team used noninvasive optical imaging. Also known as in vivo bioluminescence imaging, the technique uses an ultrasensitive camera to detect light emitted from labeled cells, even deep within animal tissues. The technology was developed at Stanford in the Contag laboratory in the mid-1990s and has been licensed by Xenogen Corp., a company founded by Contag and his wife Pamela Contag, PhD.
In the current study, funded by grants from the National Institutes of Health and a gift from John A. and Cynthia Fry Gunn, the researchers could directly see that the CIK cells carried the virus to the tumor. They also found that the combination therapy could recognize and destroy some tumors normally resistant to the CIK cells by making the tumor more susceptible to these cells.
The researchers looked at the strategy in two types of mouse models. One is a mouse model of breast cancer, in which they used mouse CIK cells to deliver the virus. The other model is a kind of hybrid; a mouse without a functioning immune system in which human ovarian tumors are growing. In these mice, the researchers tested human CIK cells.
CIK cells alone, or the virus alone, could help the mice fend off their cancer longer, but the combination therapy showed a dramatic improvement over either therapy alone.
"We were initially thinking simply that the cells could be used as a delivery vehicle to carry the virus to the tumor," said Thorne. "The nicest surprise was that there was an interaction between the virus and the immune system, and they worked synergistically to clear the tumor." The two approaches seemed to play off of each other for a more effective approach.
One of the next steps, the researchers say, is to see if their encouraging results can be translated into human therapy. They have begun the application process to begin a clinical trial in lymphoma patients and then perhaps in women with ovarian cancer in the next few years.