Vaccine/Antibody Therapy Effective in Melanoma and Ovarian Cancer

One of the shortcomings of a therapy that uses millions of identical antibodies to boost the immune system's attack on cancer cells is that many patients whose tumors recede in response to the treatment also experience serious inflammatory problems, such as severe diarrhea and rashes. In a new study, a team led by Dana-Farber Cancer Institute researchers shows that giving periodic infusions of such "monoclonal" antibodies to patients who have received a widely used cancer vaccine unleashes a strong immune response to tumors, with less-harsh side effects.

The study, to be published online by the Proceedings of the National Academy of Sciences on the week of Feb. 18, reflects efforts to untangle the benefits of monoclonal antibody therapy from its drawbacks, which result from a too-aggressive immune system assault on normal, healthy tissue. Besides demonstrating the potential usefulness of a vaccine-and-antibody approach, the new study suggests a way of refining treatment strategies even further, based on the biological events that antibody treatment sets in motion.

"We now have a better understanding of how the treatment works - by increasing the ratio of tumor-killing to immune system-suppressing cells," says the study's lead author, Stephen Hodi, MD, of Dana-Farber. "This suggests techniques for further focusing the immune system to attack the cancer with less 'fallout' for normal tissue."

The study focused on a molecular socket, or receptor, on the surface of the immune system's CD4+ T cells, which guide an attack on infected or cancerous cells. The receptor, known as CTLA-4 (for cytotoxic T lymphocyte-associated antigen), functions as a kind of shut-off valve for CD4+ T cells: When the receptor is stimulated, it causes the T cells to become inactive, quieting the immune response. Blocking CTLA-4 with a monoclonal antibody - a protein uniquely fit for the job - offers a way to keep the immune response at full force.

Studies and clinical experience have shown that CTLA-4-targeting monoclonal antibodies do increase the immune system's tumor-destroying activities in some patients. But many of these patients also develop serious inflammatory conditions, raising the possibility that the therapeutic and harmful effects of the treatment are linked.

The current study involved a cancer vaccine made from patients' own tumor cells. The vaccine is created by removing tumor cells from the body, irradiating them so they stop growing, and inserting a gene that causes them to produce a protein called GVAX. When the cells are then re-infused into patients, GVAX acts like a siren to the immune system, prompting a more energetic attack on cancer cells throughout the body.

Unfortunately, these results are rarely lasting. Most patients treated with the vaccine eventually die as their disease resumes its progress.

For that reason, researchers have begun studying whether combining GVAX vaccines with monoclonal antibody therapy could lengthen remissions, since blocking CTLA-4 could bolster the immune response spurred by the vaccine. And there was reason to think the combination could tamp down the inflammatory problems associated with antibody therapy alone.