March 14, 2008

VICC investigators discover clue to cancer drug allergies

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Christine Chung, M.D., is investigating why people in the South are more prone to severe allergic reactions to the cancer drug Erbitux. (photo by Neil Brake)

VICC investigators discover clue to cancer drug allergies

Vanderbilt-Ingram Cancer Center researchers have discovered an underlying clue to the mystery of why cancer patients in the Southeast treated with the drug cetuximab, known commercially as Erbitux, are far more likely to suffer severe allergic reactions than patients in other regions of the country.

According to the results of a study in this week's New England Journal of Medicine, it appears many of those patients already have a pre-existing antibody that reacts with the cancer drug, causing allergic reactions.

Cetuximab is a monoclonal antibody approved for use in colon cancer and squamous-cell head and neck cancer.

Christine Chung, M.D., assistant professor of Cancer Biology and lead author of the study, became curious about the drug when several Vanderbilt-Ingram patients had severe allergic reactions shortly after being infused with the substance.

Some of the reactions were life-threatening.

“When I saw my patients having these allergic reactions, they looked very much like anaphylactic reactions in terms of acuity, as you might see with something like severe peanut allergy,” said Chung. “The anaphylactic reactions are triggered by immunoglobulin E or IgE. Patients must be exposed to a substance, or antigen, before the body becomes sensitized to it and generates IgE. But these cancer patients had never been exposed to the drug cetuximab.

“I thought there must be pre-existing IgE antibodies in these patients from an antigen that is similar to cetuximab and that's why people are having reactions,” explained Chung. “While talking to other physicians, we noticed that we were seeing these reactions more frequently in the Southeast.”

Higher rates have been reported in Tennessee, North Carolina, Arkansas, Missouri and Virginia. By contrast, less than 1 percent of patients had such reactions in the Northeast.

Chung teamed with Vanderbilt-Ingram researchers Jordan Berlin, M.D., Emily Chan, M.D., Ph.D., Barbara Murphy, M.D., and Robbert Slebos, Ph.D. They contacted colleagues at the University of Virginia, Stanford, Duke, Harvard and the Allergy and Asthma Clinic of Northwest Arkansas, along with Bristol-Myers Squibb and ImClone Systems, the drug's manufacturers. The group pooled serum samples from cancer patients, as well as control subjects. Then they tested the samples for the IgE antibody.

Among 76 cetuximab-treated subjects, 25 had a hypersensitivity reaction. Antibodies against cetuximab were found in samples from 17 of these subjects. Only one of 51 subjects who did not have a reaction had the antibodies.

The geographic differences were striking. The antibodies were found in 20.8 percent of samples from control subjects in Tennessee, 6.1 percent of samples from northern California and 0.6 percent from Boston.

Next, the researchers had to figure out what the antibodies were binding to in the drug. After ruling out several options, they found the smoking gun — sugar molecules that are added to the protein during the process of making the drug in a cell line.

Chung said the finding is significant because it was the first study to show that IgE antibody can be made against sugar molecules commonly present on proteins. Now manufacturers can avoid using that cell line to create antibody-based drugs to prevent such reactions. Based on this research, a commercial assay is being developed to allow physicians to test patients for the troubling antibody before deciding to use the drug.

But another mystery still remains. What is the triggering antigen that Southerners are exposed to that causes this allergic reaction?

“I have a hunch that it might be an infectious organism, perhaps something that is more common in warm, humid weather,” Chung mused.

The scientists already have a list of possible culprits, including histoplasmosis, amoebas or other parasitic infections.