Obesity affects immunotherapy toxicity.

Obesity has pervasive effects which extend to drug interaction. A new study published in the Journal of Experimental Medicine has suggested a possible link between body fat and the risk of toxicity from immunotherapy.

The main purpose of immunotherapy drugs is to interact against , particularly in melanoma, and . These drugs use components of the immune system such as antibodies or cytokines to stimulate or suppress the immune system.

is primarily considered a disease of the aged, and yet preclinical studies generally use young, lean animal models that may not be reflective of the ‘typical’ patient,” said study lead author Annie Mirsoian. “Aging is a dynamic process that is characterized by increases in inflammatory factors, as well as a shift in body composition, where there is a gradual loss of lean muscle mass and an increase in fat accumulation, which effect how the immune system functions.”

The researchers tested mice models who were on standard diets and compared those to aged mice that were calorie-restricted throughout life.
The researchers found that calorie restriction plays an important protective role against toxicity. When laboratory aged mice ate their standard diet freely throughout life, they became obese and ultimately experienced lethal adverse reactions after receiving a systemic immunotherapy regimen.

“We know that people who are obese in general are at higher risk for complications from surgery, radiation and chemotherapy,” said study co-author Arta Monjazeb, in the UC Davis Department of Radiation Oncology. “We know that obese people have higher levels of inflammatory markers in their blood, but there is a lack of data examining the effects of obesity on treatment outcomes.”

“It is important to note, however, that the aged mice on standard diets succumbed to lethality at a quicker rate than young obese mice,” said Mirsoian. “Although our data demonstrate that obesity plays a central role in the development of adverse effects, future studies will focus on examining the aged immune system and cellular characteristics that may have enhanced the sensitivity of these mice to .”

“Obesity has become an epidemic in our society, and is now also affecting younger populations,” said Mirsoian. “Therefore, it’s likely that what the ‘typical’ patient looks like will change. Our findings demonstrate the importance of having preclinical animal models that reflect the clinical scenario. Changing the characteristics of our mouse models allowed for a more accurate determination of possible adverse reactions to therapy, and more closely modeled what has been reported in the clinic with stimulatory immunotherapies.”

Source

Annie Mirsoian, Myriam N. Bouchlaka, Gail D. Sckisel, Mingyi Chen, Chien-Chun Steven Pai, Emanuel Maverakis, Richard G. Spencer, Kenneth W. Fishbein, Sana Siddiqui, Arta M. Monjazeb, Bronwen Martin, Stuart Maudsley, Charles Hesdorffer, Luigi Ferrucci, Dan L. Longo, Bruce R. Blazar, Robert H. Wiltrout, Dennis D. Taub, and William J. Murphy. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice. Journal of Experimental Medicine, 2014 DOI: 10.1084/jem.20140116

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