Scientists have long sought to create a vaccine that uses the immune system to eradicate cancer, but the disease seemingly always finds a way around the body’s defenses. A new strategy spearheaded by City of Hope researchers, however, may offer new promise.
 Color-enhanced scanning electron micrograph showing Salmonella typhimurium (red) invading cultured human cells. (Image courtesy Rocky Mountain Laboratories, NIAID, NIH) |
In a study that appeared online April 28 in the journal Cancer Research, a team headed by the Division of Translational Vaccine Research’s Edwin Manuel, Ph.D., and Celine Blache, Ph.D., both postdoctoral fellows, and Don J. Diamond, Ph.D., director of the division, found that blocking a cancer-friendly protein improved their vaccine’s ability to destroy melanoma, the most serious form of skin cancer.
Early in 2010, Diamond and Manuel set about developing a way to deliver an effective cancer vaccine. A former postdoctoral fellow in Diamond’s lab, Mohamed El Sayed, Ph.D., currently in the Department of Diabetes and Metabolic Diseases Research, told them of an approach that used a weakened strain of Salmonella bacteria. The bacteria readily infect mice but not humans.
Using the Salmonella method, Diamond and Manuel developed a vaccine to invigorate the body’s immune response to a protein called survivin. Tumor cells overproduce survivin, which, as the name suggests, helps them stay alive longer.
While they believed the vaccine would work in principle, they still were concerned the cancer might have hidden defenses against it.
“Cancer vaccines are far more challenging to make effective than common childhood disease vaccines, because the tumors can suppress the immune response,” Diamond said. Cancer cells can send signals that allow them to evade immune cells that patrol the body.
But overcoming the immune suppression might allow a vaccine to work more effectively, the team suspected. To do that, they targeted a protein called signal transducer and activator of transcription 3, or STAT3.
Previous studies by City of Hope researchers have shown that many tumor cells produce excessive amounts of STAT3 and that the protein protects tumors from the body’s immune response.
“By knocking down STAT3 expression, we hoped to reinvigorate the immune response in the area of the tumor and boost the vaccine’s antitumor effects,” Manuel said.
As with the vaccine, the team designed a way that used Salmonella to deliver a small piece of genetic material called shRNA that could prevent tumor cells from making STAT3. They then gave mice with melanoma one of three treatments: either shRNA, the anticancer vaccine or both shRNA and vaccine.
The scientists saw little effect in the mice that received only the shRNA or the vaccine alone. In the mice that got both shRNA and vaccine, though, they found clear evidence that tumor cells were dying, and the mice survived longer than those given only the single treatments.
According to the scientists, their study is the first to demonstrate that combining a vaccine and shRNA makes them work together more effectively than either alone. If it ultimately proves fruitful, the approach could turn the bacterium Salmonella — a major cause of food borne illness — against cancer.
“Our results not only show the strategy is effective, they suggest vaccines may only work if we eliminate tumor-related immunosuppression,” Diamond said.
The team currently is developing other approaches to control melanoma growth they feel will be more powerful. These methods also should be more readily moved into clinical use, according to Diamond.
Other City of Hope authors on the study also include Rebecca Paquette, Teodora Kaltcheva, Ph.D., Hidenobu Ishizaki, Ph.D., M.D., and Joshua D.I. Ellenhorn, M.D. The study was supported by the National Institutes of Health and ThinkCure.
