Weight May Affect Toxicity of Immunotherapies

Immunotherapy is the only alternative to chemotherapy and radiation for the treatment of advanced-stage tumors and recent research has shown a correlation between weight and the toxicity of these immunotherapies. Early phase I and II clinical trials have demonstrated tumor response with adoptive cell transfer using chimeric receptor antigens, also known as chimeric antigen receptor (CAR) T-meso cells. These specialized T cells are harvested from the patient, manipulated to recognize proteins on the cancer cell’s surface, and then infused back to the patient in high concentrations.

Another form of immunotherapy is the use of monoclonal antibodies to block certain immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated protein-4 (CTLA-4). Malignant cells escape immune surveillance because of their ability to increase certain proteins on T cells that negatively regulate the immune system. CTLA-4 blockade interrupts this process, allowing T cells to remain activated, thereby recognizing the malignant cells and initiating apoptosis.

Vassiliki Papadimitrakopoulou, MD, on Adverse Events Associated With Immunotherapy in Lung Cancer

Papadimitrakopoulou is a professor at the University of Texas MD Anderson Cancer Center.

While early patient studies of immunotherapy are promising, questions remain about its toxicity profile. In particular, toxicity in association with the patient’s age and body composition has become a point of interest for researchers at the University of California Davis School of Medicine in Sacramento.

“Cancer 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 cancer patient,” said Annie Mirsoian, PhD candidate, UC Davis, who led the team involved in a study that was published in theJournal of Experimental Medicinein November 2014.¹

The team examined the toxicity profile using a mouse model more accurately reflective of the patient population receiving immunotherapies. The researchers hoped that this design would explain why discrepant toxicity results had been found between preclinical and clinical trials.

In an earlier study, Mirsoian’s team had discovered that older mice expressed increased inflammatory markers compared with their younger counterparts. When immunotherapy was administered, this compounded the inflammatory response and became lethal.

Because aging is also associated with an increase in visceral fat deposition, similar to that which occurs in obesity, Mirsoian’s team later evaluated the effect of body composition on toxicity profiles, finding that obese mice were more likely to suffer adverse effects.

The team postulated that excess fat, or adiposity, itself was a contributor to the results independent of age. To test this hypothesis, they placed mice on a calorie-restricted diet and compared them with mice on a standard diet. The mice on the standard diet became obese and experienced higher levels of toxicity after the administration of immunotherapy. These obese mice also died at a faster rate.

The findings of the study shed light on how both age and body composition interact with the immune system, particularly as it relates to cancer treatment.

“Aging is a dynamic process that is characterized by increases in inflammatory markers 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 affect how the immune system functions,”²Mirsoian said.

It is unknown how weight affects toxicity of immunotherapeutic agents in humans with cancer. Severe toxicities have been reported, including cardiac failure and fever, with less severe complications involving the nervous and gastrointestinal systems. One method for avoiding toxicity is through the use of CART-meso cells, designed to express the chimeric receptor antigen for 3 days, after which the cells return to their original state. This limits the patient’s exposure to the therapy while still appearing to provide benefit against the cancer cells.

Whether or not the observed toxicity of immunotherapies would be affected by caloric restriction or body fat reduction has yet to be studied in any clinical trial. However, the association of obesity with the development of cancer is well established in the literature.

“We know that people who are obese in general are at higher risk for complications from surgery, radiation, and chemotherapy,” stated coresearcher Arta M. Monjazeb, MD, PhD, UC Davis School of Medicine. Extrapolating the study results, it appears that immunotherapy may possibly be included in that list.

Clinical Pearls

• Toxicity of immunotherapies used in treatment of cancer in association with the patient’s age and body composition has become a point of interest for researchers.
• Researchers at UC Davis in Sacramento, California, are conducting studies in mice that more accurately represent the age and body composition of patients with cancer.
• In previous studies, older mice expressed increased inflammatory markers compared with their younger counterparts, resulting in a lethal inflammatory response when immunotherapy was administered.
• Researchers suspect that adiposity, independent of age, might be responsible for this effect, and studies are under way to evaluate this hypothesis.
• Using animal models that reflect human patient population is likely to be the first step in understanding the toxicity profile for a more accurate prediction of adverse events.

While immunotherapy is an exciting avenue for researchers to explore novel treatments against various types of cancer, there is still much to be determined before it can be approved for widespread use.

Using animal models that better reflect the patient population is likely to be the first step in understanding the toxicity profile for a more accurate prediction of adverse events.

As Mirsoian explained, “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.”

References

1. Mirsoian A, Bouchlaka MN, Sckisel GD, et al. Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice.J Exp Med. 2014;211(12):2327-2328.
2. Cancer Immunotherapy Toxic to Obese Rats. Bioscience Technology. http://www.biosciencetechnology.com/news/2014/11/cancer-immunotherapy-toxic-obese-rats. Accessed November 21, 2014.