|Researchers Find Cause of Severe Allergic Reaction
to Cancer Drug|
Reaction More Common in Specific Regions of the United States
Clinicians have been perplexed by the fact that some patients
given the drug cetuximab — an immune-based therapy commonly
used to treat persons diagnosed with head and neck cancer, or colon
cancer — have a severe and rapid adverse reaction to the
drug. Sometimes the reaction includes anaphylaxis, a life-threatening
condition characterized by a drop in blood pressure, fainting,
difficulty breathing, and wheezing. Now researchers funded by the
National Institute of Allergy and Infectious Diseases (NIAID),
part of the National Institutes of Health, have discovered that
specific pre-existing antibodies cause the severe reaction to the
drug. This discovery in turn has enabled them to explain the unusual
geographic pattern of this reaction seen among individuals in the
United States. The unusual findings of this investigation appear
in a report published in the March 13 edition of the New England
Journal of Medicine.
"These intriguing research findings not only are potentially
important to physicians treating certain cancer patients, but also
may have broader implications for the use of immunotherapies for
other diseases," notes Anthony S. Fauci, M.D., NIAID director.
NIAID grantee Thomas Platts-Mills, M.D., Ph.D., who heads the
Division of Allergy and Clinical Immunology at the University of
Virginia, led a research study to investigate the cause of the
clinical problem with cetuximab. Their newly reported findings
are of immediate importance in the care of cancer patients, says
Dr. Platts-Mills. "Because of the widespread use of cetuximab
in cancer treatment, it may be useful to pre-screen patients for
specific IgE antibodies to cetuximab to identify those who are
at risk for serious adverse reactions, including anaphylaxis."
Cetuximab is a partially humanized mouse monoclonal antibody,
which means it is produced by a single cell line and acts against
a specific protein. The drug inhibits a growth factor receptor
found on the cell surface, thereby controlling the growth of cancer
Upon reviewing the scientific literature, the research team was
intrigued by the unusual geographic distribution of patients with
anaphylaxis. For example, 22 percent of patients treated with cetuximab
in Tennessee and North Carolina had anaphylactic reactions, and
even higher rates and clusters of cases were reported from regions
of Arkansas, Missouri and Virginia. In contrast, less than 1 percent
of patients receiving cetuximab in the Northeast region of the
United States suffered such reactions.
Anaphylactic reactions are typically triggered by immunoglobulin
E (IgE) antibodies, which the immune system produces after being
sensitized by prior exposure to an allergen, a normally harmless
substance that in some people causes an abnormal immune response.
But when Dr. Platts-Mills and his collaborators further reviewed
the clinical data, they came across another unusual finding. Anaphylactic
reactions in these individuals had occurred within minutes of their
first exposure to cetuximab, suggesting that the patients had already
been primed to respond to cetuximab.
The researchers then hypothesized that these patients had pre-existing
IgE antibodies that cross-reacted with cetuximab and that these
IgE antibodies were directed against a specific sugar molecule
present on cetuximab. This hypothesis was derived, in part, from
knowledge that all people develop natural antibodies to sugars
found on foods, bacteria and viruses, although such antibodies
are of a non-IgE class, called IgM.
To test their hypothesis, Dr. Platts-Mills and his colleagues
analyzed the antibodies present in serum of 538 individuals. They
developed a technique for measuring IgE antibodies to cetuximab
and, in further experiments, proved that the IgE antibodies were
directed against sugar molecules on cetuximab.
The 538 serum samples included pre-treatment samples taken from
76 cetuximab-treated cancer patients primarily from Tennessee,
Arkansas and North Carolina. The remaining serum samples — from
individuals in Nashville, Northern California and Boston — served
as controls to investigate the geographical differences in hypersensitivity
The researchers found that among the 76 cancer patients, 25 developed
hypersensitivity reactions and 18 of these individuals showed a
positive reaction for IgE antibodies to the drug. Among the 51
serum samples from patients who did not have a hypersensitivity
reaction, only one had such antibodies. In control groups, IgE
antibodies against cetuximab were found in 21 percent of the samples
from Nashville, 6 percent of the samples from Northern California,
and less than 1 percent of the samples from Boston.
Although severe anaphylactic reactions have been reported following
treatment with several different monoclonal antibodies, this is
the first time a clear mechanism underlying such a reaction has
been defined. "Dr. Platts-Mills and his colleagues have
shown that the presence of pre-existing IgE antibodies to a specific
sugar molecule on cetuximab is highly predictive of a hypersensitivity
reaction to cetuximab," says Marshall Plaut, M.D., chief of
the Allergic Mechanisms Section at NIAID. "Furthermore, their
research answers an important question about how the local geographic
prevalence of these antibodies leads to regional differences in
anaphylactic reactions to cetuximab."
Now the researchers are looking for answers to yet another question:
What causes a high proportion of the population in certain parts
of the country to produce these particular IgE antibodies that
react with cetuximab? Research is in progress to explore if the
specific IgE antibodies are triggered by differences in regional
exposures to ticks or other parasites or to infectious organisms.
NIAID is a component of the National Institutes of Health. NIAID
supports basic and applied research to prevent, diagnose and treat
infectious diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness from potential
agents of bioterrorism. NIAID also supports research on basic immunology,
transplantation and immune-related disorders, including autoimmune
diseases, asthma and allergies.
News releases, fact sheets and other NIAID-related materials
are available on the NIAID Web site at http://www.niaid.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
C Chung et al. Cetuximab-induced anaphylaxis and IgE specific
for galactose-alpha-1,3-galactose. New England Journal of Medicine DOI: