Antibody therapy can increase the effectiveness of cancer vaccine, early studys

The benefit of some cancer vaccines may be boosted by treating patients with an antibody that blocks a key protein on immune system T cells, according to a small, preliminary study led by researchers at Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

The study, to be published online on April 1 in the Early Edition of the Proceedings of the National Academy of Sciences (www.pnas.org), tested the effect of a single injection of the antibody MDX-CTLA4 in nine patients who had previously been treated with cancer vaccines for either metastatic melanoma or metastatic ovarian cancer. The result, in every patient who had received a particular kind of vaccine, was widespread death of cancer cells and an increase in the number of immune system cells within the tumors – evidence of a potent immune system attack.

“This study makes a strong case that combined immunotherapy – consisting of a vaccine and antibodies – can elicit a potent immune response to some types of tumors in patients,” says the study’s senior author, Glenn Dranoff, MD, of Dana-Farber.

The technique was inspired by the laboratory work of study co-author James Allison, PhD, a Howard Hughes Medical Institute investigator at the University of California, Berkeley. He and his colleagues discovered that a protein, or antigen, called CTLA-4 on T cells restrains the immune system from attacking cancer cells. In a series of laboratory and animal experiments, Allison’s team showed that combining a cancer vaccine with an antibody able to block CTLA-4 resulted in an especially potent immune attack on tumors.

On the basis of those findings, Dranoff and his colleagues launched a Phase I clinical trial of the technique in a small group of patients. Because animal experiments had indicated that giving MDX-CTLA4 in combination with a vaccine might prompt the immune system to attack some normal cells, researchers decided to give the antibody to patients who had already been vaccinated.

Seven of the study participants had metastatic melanoma, a potentially fatal cancer that originates in skin cells, and two had metastatic ovarian cancer. In all three melanoma patients who had been treated with one form of vaccine, tumors showed extensive signs of cell death and were saturated with large numbers of tumor-fighting immune cells. The same results were seen in the two ovarian cancer patients who had been treated with the same type of vaccine. (The vaccine is created by loading tumor cells with a gene called GM-CSF that alerts the immune system to the tumors’ presence, prompting an anti-tumor attack.)

Of the four melanoma patients who had received a different type of vaccine based on melanoma antigens, none experienced a similar benefit, researchers found.

While none of the study participants had serious reactions to the antibody itself, some of the melanoma patients developed a mild immune reaction against normal skin cells called melanocytes, but it was not a dangerous side effect.

Previous clinical trials have shown that vaccines can be at least temporarily effective in treating metastatic melanoma and ovarian cancer, but most patients eventually succumb to their disease. One of the reasons for this may be that the CTLA-4 molecule gradually weakens the immune system’s ability to recognize and respond to tumor cells.

“By blockading CTLA-4 with antibodies, we had hoped to strengthen the immune response produced by cancer vaccines,” remarks Dranoff, who is also an associate professor of medicine at Harvard Medical School and a Leukemia and Lymphoma Society clinical scholar. “Work in the laboratory and in animal models suggested that this approach could be effective. The new study offers the first evidence that the technique has promise in human patients, although much more study will be needed to demonstrate that this is the case.”

The study’s lead author is Stephen Hodi, MD, of Dana-Farber. Other co-authors were from Massachusetts General Hospital, Massachusetts Eye and Ear Infirmary, Harvard Medical School, and Mederex, Inc.

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Funding for the research was provided in part by the Berlex Oncology Foundation, National Institutes of Health, the Leukemia and Lymphoma Society, the Cancer Research Institute, and Mederex, Inc.

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.