Center scientists have discovered a promising experimental system that could be used to develop cancer treatments that harness a patient's own immune system to fight his or her disease. Once translated to the clinic, researchers believe the method could be applied to create tumor-fighting vaccines or to produce immune-system cells that attack breast, ovarian and many other types of cancers.
The study, led by Drs. Veronika Groh and Thomas Spies and collaborators in the Immunology Program of the Clinical Research Division, focused on dendritic cells, important parts of the immune system that stimulate a wide range of disease-fighting activities in the body. For that reason, many scientists have tried to exploit the cells' protective powers to develop cancer therapies, but existing approaches for doing so have yielded limited success in the clinic thus far.
The new research, published in the May 3 issue of the Proceedings of the National Academy of Sciences, describes a method for coaxing dendritic cells to provoke a powerful anti-cancer response in the laboratory. Although the paper highlighted using the approach for melanoma, ovarian and breast cancer, it is expected to work equally well for a wide range of tumor types. Scientists in the Clinical Research Division have already begun preliminary work using the method to discover potential therapies for cancer patients.
Dendritic cells are found in many tissues of the body, where they feed upon dying cancer or other diseased cells. Once ingested, the cancer-cell components are processed into small bits, called antigens, which decorate the surface of the dendritic cell. These then act as signals to mobilize other parts of the immune system to mount a defense against the disease, said Groh, lead author of the paper.
"Many people have tried to mimic this process in the laboratory and then use it to develop treatments against specific types of cancers," Groh said. "Ideally, you want to set up a system that matches what occurs in the body as closely as possible."
The MICA method
Most attempts to artificially cause dendritic cells to ingest and display cancer antigens on their surface have focused on "loading" dendritic cells with a single antigen, a situation not at all similar to what happens inside the body. Others have tried a more realistic strategy of growing dendritic cells side-by-side with tumor cells, but the cancer cells were not reliably ingested or processed in those experiments.
Groh and colleagues observed that they could increase the likelihood that dendritic cells would swallow and process whole tumor cells using a trick based on a protein long studied in the Spies lab. The protein, called MICA, is made by many types of tumor cells but not by healthy tissue. Knowing that antibodies can help coax dendritic cells into action, the scientists coated melanoma cells with antibodies to MICA, and these cells were grown in laboratory dishes alongside dendritic cells.
The researchers found that coating the cancer cells with the antibody significantly boosted the ability of the dendritic cells to ingest and process the melanoma, ovarian and breast cancer cells.
More importantly, they found that these "primed" dendritic cells were highly effective at stimulating immune cells called T cells to seek out and destroy the tumor cells. In addition, in contrast to prior studies in which only CD8 T cells were stimulated, this new approach mobilized both the CD4 and the CD8 T cell arm of the anti-tumor response.
"This work opens up the door to many new possibilities for immune-based treatments," said co-author Dr. Cassian Yee, who is using the approach to create new therapies for ovarian-cancer patients.
There are two potential ways in which this method can be used to develop new therapies. One is to use primed dendritic cells as vaccines, since once delivered into the body they will stimulate T cells to fight cancer. A second approach is to identify the specific antigens on the primed dendritic cells that potently stimulate cancer-specific T cells, which can be grown to large quantities in the lab and infused into a cancer patient.
"What we've learned through this study is that there are many more such antigens than anyone ever expected, at least for the tumor types we've investigated," Yee said. "That means there are many potential targets for therapy — and because MICA is found on the surface of most solid-tumor cells as well as some leukemias, the approach should be widely applicable to many types of cancers."
Other Clinical Research Division investigators who contributed to the study were Drs. Yongqing Li, Daniel Cioca, Naomi Hunder, Wei Wang and Stan Riddell. The work was funded by in part by the Avon Foundation Breast Cancer Immunotherapy Research Initiative.