Does your gut biome affect your response to immunotherapy?

There’s a microscopic ecosystem inside your intestinal tract that’s made up of trillions of bacteria, viruses, fungi and other microorganisms, and scientists are just beginning to understand its enormous impact on both your physical and mental health. (It would be surprising if it didn’t have an effect — the DNA of those microorganisms vastly outnumbers the human DNA in your body!) 

Thanks to ovarian cancer patients who enrolled in a clinical trial at Roswell Park Comprehensive Cancer Center, new information is emerging about how this ecosystem, called the gut biome, impacts the effectiveness of cancer immunotherapy — and researchers are considering how it could be altered to improve treatment outcomes. 

You inherit most of your gut biome from your biological mother, but the number and kinds of microorganisms it contains will change during your life. They’re affected by factors such as your age, diet, exercise habits, exposure to alcohol and tobacco, and use of antibiotics and other drugs. All those things can reduce the number of beneficial bacteria inside of you. 

Why is your gut biome so important? 

• It helps you digest food and absorb nutrients.
• It’s involved in the development of a wide range of health issues, from allergies, asthma, colon cancer and diabetes to autism, anxiety and depression.
• It plays a key role in managing your immune system. Your intestinal tract contains up to 80% of the immune cells that help it “learn” to identify harmful germs — and cancer cells — so they can be destroyed. 

Roswell Park patients provide critical insight 

To better understand how the gut microbiome may influence the effectiveness of immunotherapy, Roswell Park launched a unique phase 2 clinical trial that enrolled 40 ovarian cancer patients whose disease had returned after multiple prior treatments. The study was led by Principal Investigator Emese Zsiros, MD, PhD, FACOG, Chair of Gynecologic Oncology.

All participants received the same treatment combination: a type of immunotherapy called an immune checkpoint inhibitor; a targeted treatment called a monoclonal antibody, to prevent the growth of new blood vessels that tumors depend on to survive; and chemotherapy. The trial demonstrated that this treatment resulted in longer-than-expected disease control in some patients, and they maintained their quality of life. Findings from the study contributed to a growing body of evidence that led to changes in national treatment guidelines with the addition of this combination therapy, which provides a new option for patients with advanced ovarian cancer. 

Throughout the study, patients provided biological samples, including stool samples, both before and during therapy. This allowed researchers to investigate whether differences in the makeup of the gut microbiome were associated with how patients responded to treatment. 

“Our objective was not only to measure clinical outcomes, but to understand the biological mechanisms behind them,” says Dr. Zsiros. “We observed that patients who experienced a longer-lasting benefit from treatment had tumors that had been penetrated by more cancer-killing immune cells, particularly CD8-positive T cells. When we combined that information with microbiome and metabolic data, distinct patterns began to emerge. These findings suggest that the gut microbiome may be part of a broader network influencing how the immune system responds to cancer therapy.” 

In analyses led by Spencer Rosario, PhD, Director of the BMPK Shared Resource in the Department of Medicine, Biostatistics and Bioinformatics, investigators examined patients’ fecal specimens and found that patients whose disease responded best to therapy had higher levels of certain bacterial species compared with those who experienced a reduced benefit. 

The team also identified differences in metabolic pathways linked to participants’ response to therapy, including pathways involved in lipid metabolism (how the body processes fats) and amino acid metabolism (how the body utilizes proteins). These processes play important roles in regulating how the immune system works, suggesting a potential biological connection between the gut microbiome and the immune system’s anti-tumor attack. 

“This study allowed us to move beyond looking at the microbiome in isolation,” says Dr. Rosario. “By combining data about the gut biome, the immune system and metabolic processes, we were able to look at the big picture and identify patterns that were consistently associated with longer-lasting response to therapy. That gives us a stronger foundation for exploring whether modifying the microbiome could eventually enhance immunotherapy outcomes.” 

Can we reprogram the immune system via the gut biome? 

The Roswell Park team plans to conduct additional clinical trials to find ways of strengthening patients’ gut biomes by increasing the number and types of bacteria associated with improved outcomes after immunotherapy. “These microbial populations may offer new avenues for improving immunotherapy response in difficult-to-treat populations,” says Dr. Rosario. That might be achieved through changes in diet or a fecal transplant, which involves transplanting stool from a healthy donor to the patient. Fecal transplant is currently FDA approved to prevent the return of a difficult-to-treat bacterial colon infection called Clostridioides difficile and is also being used in clinical trials for many physical, neurological and psychological conditions. 

In the more immediate future, Drs. Zsiros and Rosario are exploring Dielma fastidiosa, a bacterium that was identified in a higher level in patients who had a stronger response to treatment, to see if it might have the potential to “reprogram” the immune system. 

This ongoing investigation provides a hopeful new direction for patients with recurrent ovarian cancer, most of whom do not have access to therapies that might provide a cure and could help improve immunotherapy treatments for patients with other types of cancer as well. It’s another step in Roswell Park’s efforts to fight cancer using the immune system — the power inside all of us.