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Key to effective immunotherapy may lie in the gut

BY Susan Landon
MDedge News

The trillions of microscopic organisms living in the gut and their ecosystem can alter how well immune checkpoint inhibitors work, for better or for worse.

Drugs that unleash the immune system, so-called immune checkpoint inhibitors, have improved outcomes in kidney cancer and a variety of other cancers, shrinking tumors, slowing progression, and helping patients live longer. Fascinating new evidence has suggested that their effectiveness hinges in part on an unassuming organ system: the gut.

“The results that we have seen recently with combinations of checkpoint inhibitors are astounding,” says Sumanta K. Pal, MD, codirector of the Kidney Cancer Program at City of Hope, Duarte, Calif. “But it’s important to remember that a quarter of patients will actually not respond at all to these therapies and in fact just have progression. And beyond that, another group of patients will not have a profound response. So only about 46% of patients will respond to combination checkpoint inhibition, and we need new strategies for the remainder.”

Immune checkpoint inhibitors such as nivolumab (Opdivo) and ipilimumab (Yervoy) essentially take the brakes off the immune system so that it is more active in targeting tumors. But the immune system has to be functioning properly in order for these drugs to work their magic.

The gut microbiome is a complex ecosystem containing trillions of diverse microorganisms – mainly bacteria but also fungi, viruses, and others – that influence the immune response (Trends Immunol. 2012 Sep;33[9]:459-66). The colon is especially densely populated and home to at least several hundred types of bacteria (Lancet. 2003 Feb 8;361[9356]:512-9). Various factors, including illness and antibiotic therapy, can perturb the health of the gut microbiome.

Emerging evidence has suggested that certain gut bacterial profiles alter the effectiveness of immune checkpoint inhibitors.

Research has shown that simply supplementing the diet of mice with beneficial (“good”) bacteria that normally live in the gut called Bifidobacterium increases their immune system’s response to melanoma tumors (Science. 2015 Nov 24;350[6264]:1084-9). Moreover, it enhances the effectiveness of immunotherapy against the cancer, nearly halting tumor growth.

Among patients with kidney or lung cancer, the diversity and types of bacteria present in feces before starting treatment differ between those whose tumors do and do not respond to immunotherapy (Science. 2018 Jan 5;359[6371]:91-7).

In particular, those having a response are found to have greater diversity of gut microorganisms and higher levels of certain beneficial bacteria. In addition, transplantation of fecal microbiota from the patients having a response to immune checkpoint inhibitors into mice improves their response as well.

Findings have been similar among patients with melanoma who are treated with immune checkpoint inhibitors. Those achieving a response to this therapy have greater overall bacterial diversity in their gut and more beneficial bacteria (Science. 2018 Jan 5;359[6371]:104-8 and Science. 2018 Jan 5;359[6371]:97-103).

“The gut microbiome may potentially play a role in dictating responses to immune-based therapies, but I would caution any overselling of the gut microbiome at this point in time because we are really at a biomarker discovery phase,” Dr. Pal commented. “While we can certainly say that there might be a gut profile that is associated with response to immunotherapy, we don’t know whether or not that is associated with responses to other, traditional drugs used in kidney cancer. That’s one of the major limitations. We can’t yet use it to predict response and define which therapy I’m going to use.”

Research is also clarifying how external factors that affect the gut microbiome, such as antibiotic therapy, may alter the benefit of immune checkpoint inhibitors. Antibiotics are known to be harmful to beneficial bacteria in the intestine, creating an unfavorable balance of microorganisms called dysbiosis (ISME J. 2007 May;1[1]:56-66). A recent study among patients with advanced kidney or non–small cell lung cancer who were starting immune checkpoint inhibitors found that those who had used antibiotics in the past month were more likely to experience cancer progression and death (See “Immunotherapy is less effective when given shortly after antibiotics”).

Taken together, these discoveries have generated intense interest in gut-specific interventions that could one day improve the activity of immune checkpoint inhibitors and tailor treatment for individual patients (Science. 2018 Jan 5;359[6371]:32-34). Interventions under consideration or already being tested include certain diets, probiotic foods or supplements, and fecal transplant.

“I am intrigued by the possibility of having relatively inexpensive modalities, for instance, fortified yogurts and food compounds, that could drastically impact the outcome of immunotherapy. It remains to be seen whether or not that will happen or if we will have to rely on more expensive tailored products,” Dr. Pal said. “There are many efforts ongoing to develop tailored microbiome products, whether that’s fecal transplant or refined compounds that resemble the fecal microbiome, to repopulate the gut. These warrant a substantial amount of further testing before they are implemented clinically. My understanding is that that’s happening now, so it may not be long before we see some of those data emerge.”

 

An ongoing trial at City of Hope that is testing the effects of a yogurt fortified with beneficial bacteria on the gastrointestinal side effects of another type of therapy for kidney cancer will also assess whether and how it alters the gut microbiome (NCT02944617). “There are several other efforts like this taking place around the country, and all of these could potentially lead to relatively simple changes in practice to optimize outcomes with these immune-based therapies,” he says. In addition, “we are having ongoing discussions in the context of a lot of our large upcoming clinical trials about collecting stool and doing assessments of the microbiome.”

The new data on antibiotic therapy are mainly helpful in piecing together the gut microbiome and immunotherapy puzzle, according to Dr. Pal. “We have some suggestion that antibiotics may potentially reduce diversity in the gut microbiome and thereby reduce responses to immunotherapy. Having said that, I still don’t think there is any mandate to avoid antibiotics in patients receiving immunotherapy. Frankly, if you need antibiotics, you need antibiotics,” he explained. “Nevertheless, this information gives us clues suggesting that agents that will increase biodiversity may, down the line, be associated with improved responses.”