Immunotherapy for advanced cancer is gaining popularity as a treatment strategy. But scientists are now asking an important question: do biological differences between men and women influence the therapy’s effectiveness?
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Are we missing an important trick by ignoring the impact that biological sex might have on the effectiveness of immunotherapy?

Immunotherapy — a type of treatment that aims to boost the body’s own defence mechanisms against disease — has been gaining ground lately as a more effective strategy against several cancers.

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It is typically used to treat cancer in its advanced stages, when other types of treatment no longer work.

But research into the treatment is ongoing, with scientists often revealing previously unknown mechanisms that may have a bearing on how the therapy proceeds.

Now, Dr. Fabio Conforti and his colleagues from the European Institute of Oncology in Milan, Italy, suggest that in the effort to find more effective cancer therapies quickly, researchers may have glossed over an important consideration.

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Namely, that hardwired biological differences between the two sexes could have an impact on whether the treatment is successful.

Men and women’s immune systems have sex-specific characteristics that have not been properly taken into account by specialists investigating the effectiveness of immunotherapy, write Dr. Conforti and team in an article published in The Lancet Oncology.

“Both sex and gender can potentially affect the strength of the body’s immune response,” argues Dr. Conforti.

On average, women mount stronger immune responses than do men, which results in more rapid clearance of pathogens, explaining the lower severity and prevalence of many infections in women […] On the other hand, women account for roughly 80 [percent] of all patients with systemic autoimmune diseases worldwide.”

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Dr. Fabio Conforti

“Therefore,” he continues, “it’s possible that differences in the immune system of women and men could be relevant to the natural course of chronic inflammatory conditions such as cancer, and potentially how they respond to drugs.”

Skewed male to female ratio in clinical trials

Dr. Conforti and team conducted a meta-analysis of 20 randomized trials, assessing 11,351 patients — comprising 7,646 men and 3,705 women — with various forms of advanced or metastatic cancers.

All the study participants had received treatment with immune checkpoint inhibitors (ipilimumab, tremelimumab, nivolumab, or pembrolizumab), which are drugs that help to boost a person’s immune response to cancer.

The cancer types that the participants were treated for included skin cancer, kidney cancer, cancer of the bladder, head and neck cancer, and lung cancer.

Just by looking at the male to female ratio in the clinical trials they analyzed, the scientists point out that there is an obvious imbalance; the studies, on the whole, tended to include far greater numbers of male patients.

The under-representation of women in clinical trials has been pointed out by many specialists, who have emphasized that this gap may turn out to be problematic when it comes to approving and releasing drugs for the general population.

Although, in analyzing the existing studies, Dr. Conforti and team noted that immunotherapy proved more effective than control therapies for both men and women. They also found that, on average, survival rates were higher among men, compared with women.

“An individual’s prognosis,” explains Dr. Conforti, “will depend on multiple variables including type of cancer and the drugs used, and immunotherapies continue to be the standard treatment for several cancers, with survival often far better than other drugs.”

But although the researchers noted some discrepancies in the benefits afforded by immunotherapy to men versus women, they are wary of recommending the application of differential treatments as yet.

“Treatment for women,” Dr. Conforti states, “should not [be] altered based on these findings, rather we need to understand more about the mechanisms to ensure that these novel treatments can be optimized for both men and women.”

‘Trials rarely take sex into account’

Another observation made by the authors is that there seem to be certain sex-specific differences in how the immune system functions. Those differences occur at cellular level, and they may be driven in part by distinct hormonal activity.

And certain checkpoint inhibitor pathways, previous studies have suggested, may be altered in response to different sex hormones.

Yet “[d]espite the available evidence on the potential role played by sex in influencing how drugs work, trials testing new therapies rarely take sex into account,” notes Dr. Conforti.

“Immune checkpoint inhibitors,” he explains, “have revolutionized cancer treatment, showing higher efficacy than standard therapies in several cancers. As we seek to improve immunotherapy further by identifying predictive biomarkers of response, sex differences should be further investigated.”

Still, the new meta-analysis does face some limitations, by the authors’ admission. These include the fact that their findings are based on the data reported in studies, rather than on medical information sourced directly from the patients.

In the editorial comment that accompanies the article, Omar Abdel-Rahman — who works in the Ain Shams University in El-Abaseya, Egypt, and the University of Calgary in Canada — stresses that the meta-analysis amalgamates data related to many different types of cancer tumors, all of which may have vastly different characteristics in men versus women.

“[W]ithin each solid tumor,” he explains, “there are a multitude of baseline characteristics that might differ in their distribution between men and women, and these baseline characteristics have been reported to affect outcomes of patients treated with immune checkpoint inhibitors.”

“Moreover,” he warns, “there are also lifestyle or behavioral characteristics that differ between men and women that might also have confounding effects.”

And, as Abdel-Rahman goes on to explain, “Although the article by [Dr.] Conforti and colleagues is a thought-provoking and hypothesis-generating piece of work, caution needs to be exercised before jumping directly to radical conclusions and before changing the current standard of care among approved indications for immune checkpoint inhibitors.”