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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
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
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
"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
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