Modifying the Gut Microbiome to Improve Immunotherapy Treatment Response (ASCO Microbiome Session, Part 1)

I have been remiss in writing about cancer and the microbiome. To be fair, I’ve been diving into other areas of advocacy, traveling a ton, and well, not making time for something I both enjoy and, as I was recently reminded, has been helpful in other’s understanding and exploring the roles of the microbiome in breast cancer. No excuses, onward!

This post and the next will discuss the very first American Society for Clinical Oncology (ASCO) session on the microbiome and cancer (yes, that was two plus months ago haha). It’s impossible to sum up everything, so we will focus on two studies where the goal was to modify the gut microbiome in order to improve treatment response. Nothing breast cancer specific, but both studies were done in the advanced (metastatic) setting. Additionally, both studies examine response to an immunotherapy drug called nivolumab/Opdivo which is not approved to treat breast cancer, but is similar in structure and action to pembrolizumab/Keytruda, which is used to treat triple negative breast cancer. Specifically, these are both monoclonal antibodies that bind to the PD-1 receptor protein on immune cells called T-cells; this leads to the T-cells becoming more likely to destroy cancer cells. PD-1 inhibitors are also called immune checkpoint inhibitors. Ok, so on to the microbiome portion….

 

In this first post we will look at fecal microbiota transplants (FMTs). These are interventions where healthy microbiota from one person are given to a person with an unhealthy microbiome (which, frankly, is not always easy to determine). The healthy donor microbiome can be introduced in several ways. It can go via the upper gastrointestinal tract- as a pill or using a tube, or via the lower gastrontestinal tract, introduced via a tube inserted rectally (see below). While pills might not sound palatable, there is no taste, and much easier to pop a pill, but I digress. So, all this, for what? Well, FMTs are now FDA approved to treat a bacterial infection called Clostridium difficile (C. diff for short) that causes severe diarrhea. Many strains of C. difficile are antibiotic resistant, and the disease can be deadly.

 

Fecal microbiota transplant processes. Image from Bou Zerdan et al. 2022. https://doi.org/10.3390/cancers14030691 CC BY 4.0

 

A lot of work has been done in modifying the microbiome to improve immunotherapy outcomes in melanoma. But what about other cancers? At ASCO Dr. Sook Ryun Park presented the results of a study that investigated fecal microbiota transplants (FMTs) from immunotherapy responders to immunotherapy non-responders. This is the last time I will respond to patients as responders or non-responders- it's the tumor or the cancer that doesn't respond as that is what was directly measured.

 

This was a small study with 13 FMT recipients, who all had advanced, solid tumors (gastric, esophageal, or hepatocellular) and had previously received a PD-1 inhibitor, but their tumors had not responded. The donor fecal material for the transplant came from patients whose tumors had responded to PD-1 therapy. The donor fecal material was given to the recipients from one to four times, from one or multiple donors.

 

In terms of side effects, there was some mild to moderate (grade 1-2) itching in about half the patients and one patient experienced more severe (grade 3) gastritis (inflammation and swelling of the stomach). Otherwise, there were no additional grade 3-4 adverse events.

 

After FMT and reintroduction to a PD-1 inhibitor, specifically nivolumab/Opdivo, did the drug work? Remember all these patients had already been treated with a PD(L)-1 inhibitor and had progression. Could the FMT resensitize the tumors to this drug? Well, one of the 13 patients had a partial response (some tumor shrinkage) and five had stable disease (neither growth nor shrinkage of the tumor). For those keeping track, that’s a 46% control rate. In my mind, for an intervention (FMT) with few side effects and a 46% control rate. I’d enroll in this or the next study.

 

Patient #7, the one whose tumor shrank and was stable after FMT + nivolumab/Opdivo was further studied to determine why they had such a good response. It turns out that patient #7’s tumor didn’t shrink until after the second FMT from a different donor (donor #5)! The authors thought the immune system might be responsible and so looked at cells and cell signals related to immunity.  What they found were changes in the patient’s immune system- an increase in cell killing white blood cells (CD8/cytotoxic T-cells) and a decrease in immune dampening white blood cells (regulatory T-cells). And there were marked differences in immune signaling (cytokines).  

 

What was so special about the second FMT from donor #5? Were there specific bacterial species present? The authors compared the bacterial species among donors and recipients and found that a bacterial strain, Prevotella merdae Immunolactis was only present in donor #5. Donor #5 was the donor for the second FMT to patient #7- the one that caused the decrease in tumor size. This bacterium was also present in a patient (#6) who received an FMT from donor #5. Patient #6's tumor did not shrink but did remain stable after FMT.

 

Were there differences in the gut microbiota of patient recipients #6 and #7? The authors found that Lactobacillus salivarius was present in recipient #6 both before and after FMT from donor #5…perhaps this bacterium was suppressing the effectiveness of the FMT? Further laboratory studies in cell culture and mice showed that P. merdae increased an immune response that leads to tumor death, while L. salivarius inhibited this response. I appreciated this study as it did not stop at finding differences in bacterial species, but went further into mechanistic and other studies using cultured bacteria.

 

Interestingly, a study recently found that P. merdea may be a biomarker for immunotherapy response in melanoma patients (Olekhnovich et al. 2023). It was consistently found in previous studies and their own to associate with response to immunotherapy, but Olekhnovich et al. decided to exclude it from the final analysis because the fold difference between responders and nonresponders wasn't great enough.

 

So what does all this mean? First, this is a small study that generated a lot of hypotheses- interesting findings that need to be tested to determine not only if they are reproducible, but if they hold up under further and different experimentation. For example, what if patients received only P. merdae Immunolactis; would this be sufficient to resensitize tumors to PD-1 immunotherapy? Would it only occur if L. salivarius is absent in the patient’s gut already? Are these the only bacterial species that are responsible? And, as importantly, how are these bacterial species causing this resensitization to PD-1 inhibitors? Are they producing specific chemicals or metabolites that signal the body’s immune system to respond to the tumor? Are they interacting with other bacteria, fungal or human cells in the gut (or elsewhere in the body), and that is leading to the immune response? What is the role of diet here? Do we know what the patients were eating/feeding their new microbes from the FMT? As Dr. Wargo has shown, increasing fiber alone is enough to lead to a better response to immunotherapy in melanoma patients.

 

In other words, it’s complex. But teasing out the mechanisms will lead to better targeted microbiome therapies that will likely lead to increased effectiveness, something that is showing promise, and I will talk about in my next blog post. Because of course I thought I could fit two presentations in one blog post, and I was wrong! 

 

Stay tuned for part 2, where we will look at another study presented in this session at ASCO- this time looking at the effects of a single strain of bacteria on nivolumab immunotherapy response. Yup, a probiotic. 

 

Questions? Comments? Please feel free to post on the blog, email me at beumerae@gmail.com, or you can find me on Twitter/X @amybeumer.

 

References

Bou Zerdan, M., Niforatos, S., Nasr, S., Nasr, D., Ombada, M., John, S., Dutta, D., & Lim, S. H. (2022). Fecal Microbiota Transplant for Hematologic and Oncologic Diseases: Principle and Practice. Cancers, 14(3), Article 3. https://doi.org/10.3390/cancers14030691

Park, S.R., Kim, G., Kim, Y., Cho, B., Kim, S., Do, E., Bae, D., Kweon, M.,  Song, J.S., Park, H. (2023) Fecal microbiota transplant conbined with anti-PD-1 inhibitor for unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor. American Society of Clinical Oncology Meeting.

Olekhnovich, E. I., Ivanov, A. B., Babkina, A. A., Sokolov, A. A., Ulyantsev, V. I., Fedorov, D. E., & Ilina, E. N. (2023). Consistent Stool Metagenomic Biomarkers Associated with the Response To Melanoma Immunotherapy. MSystems, 8(2), e01023-22. https://doi.org/10.1128/msystems.01023-22