Immunotherapy Toxic in Obese Mice

Immunotherapy that is effective against tumors in young, lean mice can cause lethal inflammation in obese mice, according to a recent study (J Exp Med 2014;211:2373–83). The findings suggest a possible link between weight and adverse events in patients treated with some types of immunotherapy.

“Most people diagnosed with cancer are over age 65 and many are overweight, yet the vast majority of studies using the mouse as a preclinical tool use young, lean mice,” says senior author William Murphy, PhD, professor and acting chair in the department of dermatology at the University of ­California, Davis, in Sacramento. Indeed, for many cancers, studies indicate more than two thirds of people diagnosed with cancer are overweight or obese.

Turning a patient's immune system against their own cancer has produced impressive responses for some patients, while others have experienced severe toxicities not previously seen in animal studies. To study this inconsistency, researchers adjusted their mouse model to more accurately reflect today's typical cancer patient: older and overweight.

They first compared aged, 18-month-old mice on standard, all-you-can-eat diets with aged mice on calorie-restricted diets, treating both groups with anti-CD40/IL2 immunotherapy. The aged obese mice all died within 2 days, succumbing to a severe immune over­reaction called a cytokine storm. Calorie-restricted aged mice, however, all survived the 12-day treatment regimen.

Elizabeth Repasky, PhD, a professor of immunology at Roswell Park Cancer Institute in Buffalo, NY, calls the experiments “groundbreaking” because they consider the mouse that is bearing the tumor rather than just the tumor itself, making the mouse model more predictive of what is being seen in patients.

“For too long in cancer research, we haven't been paying enough attention to the basic physiology of the mouse,” says Repasky, who was not involved in the study. “We're using mice that are the equivalent of a thin teenager because it's too expensive to study older overweight mice.”

Follow-up experiments showed that obese, 2-month-old mice also experience toxic effects. Young obese mice died within 4 days of treatment, whereas young lean mice survived.

“Fat appears to trump age,” says Murphy. He notes that although it is too early to extrapolate the findings to humans, weight and age are variables that may need to be considered during cancer therapy assessments.

Being obese, however, may not necessarily make a patient ineligible for immunotherapy. The researchers found that giving young obese mice etanercept (Enbrel; Amgen)—an autoimmune-disease drug that blocks the inflammatory cytokine TNF—with immunotherapy prevented the toxic effects.

As with aging, obesity puts the body into a chronic inflammatory state, changing how the immune system works. Prior infections also shape how the body reacts to immune insults. Murphy and his colleagues are now accounting for these factors as part of immunotherapy experiments in a large outbred canine model.

“There needs to be a bigger push to look at how aging and obesity impact the immune system,” Murphy says, “because these variables are going to greatly affect our ability to use the immune system to fight cancer.”

For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.