Obese patients do better in certain treatments

Being obese is bad for your health, right? Not necessarily, at least when it comes to a very special kind of cancer treatment, according to authors of a perspective piece published in the journal JAMA.

William Murphy, from the University of California Davis, and Dan Longo, from Harvard Medical School, both in the US, point to mounting evidence that for people getting a cancer therapy called “checkpoint blockade”, being on the hefty side could actually increase survival.

It’s a claim that verges on heretical, given the well-deserved bad press garnered by the obesity epidemic. Two-thirds of adults in many developed countries are overweight or obese, raising their risk for a swag of illnesses, including heart attack, stroke and high blood pressure.

The claim also sits uneasily with the fact that obesity ups the risk for some cancers.

So, what is checkpoint blockade, and how might a few extra layers make it work better?

It is one of a class of cancer treatments known as “immunotherapy”, so named because they enlist the body’s own immune cells in the battle against the disease. One of those immune warriors is the T-cell, whose job it is to take out foreign invaders such as infections. T-cells also have a strong dislike for cancer cells.

Fortunately, T-cells don’t attack fellow citizens, the body’s own cells, and that is because of an ingenious quirk. They have proteins on their surface called “checkpoints” that, when they bind to proteins on healthy cells, signal the relationship is friendly. Think of it as a handshake to say “Bro, we’re good”.

But cancer cells can express the friendly protein too, bamboozling the T-cell into giving them a bro hug rather than a lethal slug.

Here’s where checkpoint blockade kicks in.

Checkpoint inhibitors stop the handshake so T-cells can see cancer cells for the imposters they really are, and wipe them out. These drugs have shown great promise in a number of cancers, including melanoma and lung cancer.

But there is a problem. Some people either don’t respond or have rare side effects that are sometimes fatal. Hence the push for a precision approach that picks out who might do best with which treatment.

That can involve testing tumours for biomarkers, but it also happens at the big-picture level. Researchers want to peg down whether age, sex, or body weight might influence treatment response.

That last one has been throwing up some intriguing findings. A study published in January in the journal Nature Medicine found obesity generally worsens tumour outcomes. But it also found mice and humans with a range of cancers did better with checkpoint therapy if they were obese, something the authors called “paradoxical”.

Another recent study of people with melanoma found a survival advantage for obese patients getting immunotherapy.

The findings are challenging the status quo.

“Checkpoint blockade is a new therapeutic approach in which obesity can be now regarded as a potentially positive prognostic factor,” write Murphy and Longo.

Commenting on the editorial, Barbara Fazekas de St Groth from the University of Sydney in Australia points out nuances in the melanoma study.

“The effect of obesity differs between men and women,” she says.

“For the most common therapy … overweight or obese men do better than those in the normal weight range, equalling the survival rate of women in all three weight categories.”

She also notes that for a related treatment, “the survival of women at any BMI is similar to normal and overweight men, and only obese men do better”.

“These mixed results indicate the complexity of the factors that influence patient responses to immunotherapy, and the need for further research to determine whether we can pinpoint where all these factors intersect,” she says.

A big question, of course, is how obesity might confer an advantage in checkpoint therapy. Murphy and Longo note that “a high BMI environment is nutrient-rich”, which could fuel the immune response.

While affirming that “obesity should still be viewed as having a generally adverse effect on health” they go on to make a conclusion that could prompt a serious rethink in the medical fraternity.

“Ultimately, these studies demonstrate that the concept of obesity in human health and disease should be re-evaluated and perhaps adjusted,” they write.

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