A high-fiber diet may improve the response of melanoma patients to immunotherapy

A diet rich in fiber may help some people being treated for melanoma respond to immunotherapy treatment by influencing the gut microbiome, according to a new study led by researchers at the Center for Cancer Research at the National Cancer Institute (NCI), part of the National Institutes of Health, and the University of Texas MD Anderson Cancer Center. Results from the study, which analyzed both people with melanoma and mouse models of the disease, appear in Science.

Among patients with advanced melanoma who underwent immunotherapy with immune checkpoint blockers, those who consumed at least 20 grams a day of dietary fiber survived the longest without their disease progressing. In contrast, use of probiotic supplements appeared to lessen somewhat the effectiveness of immune checkpoint blocker regimens. Probiotics are live microorganisms typically consumed as a supplement to improve gut health.

“The data suggest that one can target the composition of the gut microbiota and affect the ability of the patient to respond to immunotherapy,” said Giorgio Trinchieri, M.D., chief of the Laboratory of Integrative Cancer Immunology in NCI’s Center for Cancer Research, one of the study’s coleaders. “Consuming a diet rich in fiber, like fruits, vegetables, and legumes, could improve your ability to respond to immunotherapy.”

Immunotherapy with immune checkpoint blockers helps restore the immune system’s natural ability to recognize and kill tumor cells. These drugs have been transformative in melanoma, improving how long some people with advanced disease live, sometimes by years. However, for many patients, immune checkpoint blockers fail to stop their tumors from growing. Several studies have suggested that the composition of the bacteria in the gut may influence the response to immunotherapy.

“The question is, can we change the composition of the type of bacteria in the gut and improve the ability of the patient to respond?” Dr. Trinchieri said.

In a previous study, Dr. Trinchieri and a different group of collaborators showed that some people with melanoma who initially did not respond to treatment with an immune checkpoint blocker did respond after receiving a fecal transplant from a patient who had responded to the drug. The fecal transplant, they concluded, had introduced different gut bacteria that helped make it easier for immune cells to invade and kill their tumors.

“Dietary fiber intake and use of probiotic supplements have also been shown to affect the composition of gut bacteria. More cancer patients are taking probiotic supplements in an effort to improve their gut health, but little is known about how probiotics—which basically change the ecology of the gut bacteria—impact immunotherapy response,” he said.

The connection between fiber intake and immunotherapy response has also been unclear. However, a recent study led by Romina Goldszmid, Ph.D., also of NCI’s Center for Cancer Research, showed that mice fed a diet rich in pectin, which is a fiber abundant in apples, were able to stave off tumor growth by activating immune cells and reprogramming the tumor microenvironment.

In the new study, Dr. Trinchieri and study co-leads Carrie R. Daniel, Ph.D., M.P.H., and Jennifer A. Wargo, M.D., of the University of Texas MD Anderson Cancer Center, and their collaborators looked at the composition of fecal microorganisms (the gut microbiota), dietary habits, and probiotic supplement use among patients who were being treated for advanced melanoma with immune checkpoint blockers.

Among the 128 patients whose dietary fiber intake was known, those who reported consuming at least 20 grams of dietary fiber per day (an amount the researchers designated as “sufficient” for the purposes of this study) lived longer without their cancer progressing than those who consumed less dietary fiber. Every 5-gram increase in daily dietary fiber intake corresponded to a 30% lower risk of progression of the disease.

The researchers also looked at the impact of dietary fiber on the response to treatment with anti-PD-1 drugs, a category of immune checkpoint blockers, in mouse models of melanoma. To mimic the different diets in the melanoma patients, they fed mice either a fiber-rich or a low-fiber diet, injected the mice with melanoma cells, and then treated the mice with anti-PD-1 therapy. Mice given the fiber-rich diet had delayed tumor growth after anti-PD-1 treatment, compared with mice given the low-fiber diet.

The researchers then repeated the experiments in germ-free mice—that is, mice that have no bacteria in their guts.

“In germ-free mice, the diet made no difference in the immunotherapy response,” Dr. Trinchieri said. “That suggests that the diet is affecting the response to immune checkpoint therapy by changing the composition of the gut microbiota.”

Dr. Trinchieri noted that one possible mechanism through which dietary fiber exerts its beneficial effect is by increasing the types of bacteria in the gut, such as Ruminococcaceae, that produce high levels of certain short-chain fatty acids that have an antitumor effect.

“We did see an increase in one of these short-chain fatty acids, propionate, in mice that were fed a high-fiber diet,” Dr. Trinchieri said. “Moreover, patients whose cancer responded to immunotherapy had a greater abundance of Ruminococcaceae bacteria in their gut microbiota compared with those who did not respond to therapy.”

The researchers also looked at the impact of probiotics on gut bacteria in the mouse model of melanoma. Mice fed probiotics had a reduced response to treatment with anti-PD-L1 drugs and developed larger tumors than control mice. Further analysis showed that mice fed probiotics had lower levels of tumor-killing immune cells, suggesting a weakened immune response.

In the human study, nearly one-third of the patients reported they had taken a probiotic supplement within the past month. Although the researchers noted that the small sample size and variety of probiotics used by the patients made it difficult to draw definitive conclusions about the association between probiotic use and response to immune checkpoint blockers, they did observe that patients who consumed the highest levels of dietary fiber with no probiotic use survived the longest.

“The impact of dietary fiber and probiotics on the gut microbiota is only part of the bigger picture,” Dr. Trinchieri cautioned. “Many factors can affect the ability of a patient with melanoma to respond to immunotherapy. However, from these data, the microbiota seems to be one of the dominant factors. The data also suggest that it’s probably better for people with cancer receiving immunotherapy not to use commercially available probiotics.”

ASCO 2018: Major trial is first to show benefits for immunotherapy in some men with prostate cancer

A major clinical trial has become the first to show benefits of immunotherapy in prostate cancer – for some men with advanced, otherwise untreatable disease.

Researchers showed that a subset of men who had run out of all existing options for treatment survived much longer than expected when taking immunotherapy.

Some 11 per cent of men with very advanced prostate cancer are still benefiting from the immunotherapy ‘checkpoint inhibitor’ pembrolizumab after a year – with many of them showing impressive remissions and prolonged disease control.

The international trial, led by a team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, could lead to a subset of prostate cancers joining the list of cancers that can be treated with immunotherapy.

Of the 258 men on the trial with advanced prostate cancer receiving pembrolizumab, 38 per cent of men were still alive after a year and 11 per cent are still receiving the treatment a year after the trial began without seeing their cancer grow.

The research, presented at the American Society of Clinical Oncology annual meeting in Chicago, also revealed vital clues for how to pick out the subset of men who could benefit.

Previous trials of immunotherapy in prostate cancer had been unsuccessful – but the latest study looked back at the genetics of the tumours, and found there are some particular groups of patients that might benefit.

Overall, only 5 per cent of men in the trial saw their tumours actually shrink or disappear after treatment, but the proportion of responders was higher in a small group of men whose tumours had mutations to genes involved in repairing DNA.

The team at The Institute of Cancer Research (ICR) and The Royal Marsden believe that this subset of men with prostate cancer could benefit from immunotherapy, although more evidence is needed.

They are planning a new trial of pembrolizumab specifically to assess whether it is effective in men who have DNA repair mutations in their tumours.

Tumours that have mutations in specific genes involved in repairing DNA may acquire more genetic mutations as they multiply than other cancers.

Researchers at the ICR and The Royal Marsden believe that these ultra-mutant cancer cells may be particularly easy for the immune system to recognise, since they will look different from healthy cells.

The findings are in line with data from other cancer types, such as bowel cancer, where tumours with defects in DNA repair mutations are more susceptible to immunotherapy.

The study, funded by Merck Sharp & Dohme, compared the effectiveness of pembrolizumab in men whose tumours had a protein called PD-L1 on the surface of their cancer cells and those whose tumours did not.

Targeting PDL-1 activity with an immune checkpoint inhibitor takes the ‘brakes’ off the immune system, setting it free to attack cancer cells.

But the study found testing for PD-L1 was not sufficient to tell which patients would respond to treatment.

There was some evidence that testing for another protein called PD-L2 could be a better marker of whether men will respond, but this will need to be tested in further clinical trials.

Professor Johann de Bono, Director of the Drug Development Unit at The Institute of Cancer Research, London, and at The Royal Marsden NHS Foundation Trust, said:

“In the last few years immunotherapy has changed the way we treat many advanced cancers – but up to now no one had demonstrated a benefit in men with prostate cancer. Our study has found that immunotherapy can benefit a subset of men with advanced, otherwise untreatable prostate cancer, and these are most likely to include patients who have specific DNA repair mutations within their tumours.

“We are planning a new clinical trial, specifically in men with prostate cancer whose tumours have mutations in DNA repair genes, to see if immunotherapy can become a standard part of their treatment. It’s exciting that immunotherapy could offer some men more time with their loved ones where they have such advanced disease that they have run out of existing treatment options.”

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, said:

“Immunotherapy has proven to be a smarter, kinder treatment for many types of cancer – but it still only works for a minority of patients. The challenges we now face are how to predict in advance who will benefit, and how to make immunotherapy work for more people.

“One of the major challenges with immunotherapy is that we don’t have many reliable tests to pick out who will benefit. This new trial has found that testing for mutations in DNA repair genes could be valuable marker of who will respond. If we can prove that in the planned new trial, it should be possible to provide some men with advanced prostate cancer with an exciting new treatment option.”

Michael English, 72, was treated with pembrolizumab at The Royal Marsden’s West Wing Clinical Research Centre in 2016. He said:

“I was diagnosed with prostate cancer in 2005, and over a number of years I had hormone therapies, radiotherapy and chemotherapy, including treatment in research trials. Professor de Bono recommended pembrolizumab based on a genetic test and after only a few three-weekly cycles, we were astonished when scans showed that the tumour had become undetectable. As I responded so well to pembrolizumab, I was then able to have colorectal surgery (colostomy) for small holes (fistulas) in my intestine and today I’m effectively cancer-free.

“Personalising my treatment in this way, based on the genetic make-up of the tumour, essentially saved my life. With a fourth grandchild on the way, my wife and I can now plan for the next 20 years, instead of the next two.”