From Our 2008 Archives

Combo Treatment Best for Melanoma, Advanced Ovarian Cancer

TUESDAY, Feb. 19 (HealthDay News) -- Combining periodic infusions of antibodies with a widely used cancer vaccine appears to be more effective and less harsh with melanoma and advanced ovarian cancer patients than using either treatment on its own, a new study shows.

Besides demonstrating the potential usefulness of a vaccine-and-antibody approach, the study -- published online in this week's issue of the the Proceedings of the National Academy of Sciences -- suggests a way of refining treatments 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," study author Dr. Stephen Hodi, of Dana-Farber Cancer Institute in Boston, said in a prepared statement. "This suggests techniques for further focusing the immune system to attack the cancer with less 'fallout' for normal tissue."

Previous studies and clinical experience have shown that certain monoclonal antibodies increase the immune system's tumor-destroying activities in some patients but can also give patients serious inflammatory problems, such as severe diarrhea and rashes.

Hodi's research team focused on a molecular 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), acts as a kind of shut-off valve: When the receptor is stimulated, it causes the T-cells to become inactive, quieting the immune response. Blocking CTLA-4 with a monoclonal antibody offers a way to keep the immune response at full force.

The team looked at a cancer vaccine made from patients' own tumor cells. The tumor cells are irradiated so they stop growing, and a gene in inserted so they 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.

Since blocking CTLA-4 could bolster the immune response spurred by the vaccine, researchers studied whether combining GVAX vaccines with monoclonal antibody therapy could lengthen remissions and quell the inflammatory problems associated with antibody therapy alone.

"Using a vaccine to provoke a stronger immune response to cancer may enable us to use lower levels of CTLA-4 blockers, which could reduce the severity of their side effects," Hodi explained.

The new study tested the combination on 11 melanoma patients. They were infused with a CTLA-4-blocking antibody one to four months after receiving GVAX, and every two to three months thereafter, as needed.

In contrast to previous, more intensive antibody doses, none of the patients had severe side effects, although they all developed mild, low-level inflammatory conditions (usually a rash that went away in a few days). Moreover, in eight participants, tumors throughout the body either receded or became stable. The three other patients experienced less dramatic improvements that became apparent after several months of therapy.

Similarly encouraging results were obtained in nine patients with advanced ovarian cancer, although two of them did develop severe inflammatory problems. Although large die-offs of tumor tissue were less common than in the melanoma group, some of the ovarian cancer patients did experience such results.

-- Kevin McKeever

SOURCE: Dana-Farber Cancer Institute, news release, Feb. 18, 2008.

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