Stephen Hodi, MD

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.

"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 explains.

In an earlier study, he and his colleagues demonstrated that a single infusion of anti-CTLA-4 antibodies caused extensive tumor destruction in all five metastatic melanoma and ovarian cancer patients who had previously been immunized with a GVAX vaccine.

The new study, a joint effort of Dana-Farber's melanoma program and Cancer Vaccine Center, tested the combination in a larger number of participants. Eleven melanoma patients were infused with a CTLA-4-blocking antibody (Ipilumimab®) 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 of the 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.

To understand what was happening at a basic cellular level, researchers studied tumor samples from six patients following antibody treatment. They found that tumor death was greatest in samples with high ratios of CD8+ T cells — the foot soldiers of immune system attack — to FoxP3+ regulatory T cells, which can reduce the immune response.

"Our results suggest that combination therapies of GVAX vaccine and CTLA-4-blocking antibodies could be enhanced by agents that target regulatory T cells such as FoxP3+," remarks Hodi, who is also an assistant professor of medicine at Harvard Medical School. "Future work will focus in that direction."

The study's senior author is Glenn Dranoff, MD, of Dana-Farber. Co-authors include: Marcus Butler, MD, Andrea Kruse, Suzanne MacRae, MPH, Marybeth Nelson, RPA-C, Christine Canning, PA-C, Donna Neuberg, ScD, and Nikhil Ramaiya, MD, of Dana-Farber; Darryl Oble, MD, PhD, Martin Mihm, MD, and Michael Seiden, MD, PhD, of Massachusetts General Hospital; Frank Haluska, MD, PhD, of Tufts-New England Medical Center; Israel Lowy, MD, PhD, and Alan Korman, of Medarex, Inc.; Sara Russell, MD, and Michael Jaklitsch, MD, of Brigham and Women's Hospital; Teresa Chen, MD, of the Massachusetts Eye and Ear Infirmary; and James Allison, PhD, of Memorial Sloan-Kettering Cancer Institute and the Howard Hughes Medical Institute.

Financial support for the study was provided by the National Cancer Institute and the Gruszka Cohen Family Fund for Melanoma Research, established by Dana-Farber Trustee Thalma Cohen de Gruszka.

Dana-Farber Cancer Institute (www.dana-farber.org) 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.