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South Korean Study Finds Fecal Microbiota Transplants May Help Patients with Gastrointestinal Cancers That are Resistant to Immunotherapies

Study findings could lead to improved treatments for broad range of cancers and the need for microbiome testing by clinical laboratories to guide clinicians

Is it possible that there is a connection between an individual’s gut microbiota and the ability to fight off gastrointestinal (GI) cancer? Findings from a preliminary research study performed by researchers in South Korea suggest that a link between the two may exist and that fecal microbiota transplants (FMTs) may enhance the efficacy of immunotherapies for GI cancer patients. 

The proof-of-concept clinical trial, conducted at the Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea, analyzed how an FMT could help 13 patients with metastatic solid tumors that were resistant to the anti-PD-1 antibody drug known as nivolumab (Opdivo). Anti-PD-1 drugs are immunotherapies that help treat cancer by improving an individual’s immune response against cancer cells. 

Four of the trial participants had gastric cancer, five had esophageal cancer, and the remaining four had hepatocellular carcinoma. The patients were given a colonoscopy to implant the FMTs. The recipients also received antibiotics to reduce the response of their existing microbiotas.

The FMT donors also had gastric cancer, esophageal cancer, or hepatocellular carcinoma. Prior to donating their fecal matter, the donors experienced complete or partial response to the anti-PD-1 drugs nivolumab or pembrolizumab (Keytruda) for at least six months after receiving initial treatments. 

The researchers published their study, titled, “Fecal Microbiota Transplantation Improves Anti-PD-1 Inhibitor Efficacy in Unresectable or Metastatic Solid Cancers Refractory to Anti-PD-1 Inhibitor,” in the journal Cell Host and Microbe.

“This research highlights the complex interplay between beneficial and detrimental bacteria within the gut microbiota in determining treatment outcomes,” co-senior study author Hansoo Park, MD, PhD, Assistant Professor, Biomedical Science and Engineering, Gwangju Institute of Science and Technology, told The ASCO Post. “While the connection between gut microbiota and immune response to cancer therapy has been a growing area of interest, our study provides concrete evidence and new avenues for improving treatment outcomes in a broader range of cancers,” he added. Further studies may confirm the need for microbiome testing by clinical laboratories to guide clinicians treating patients with colon cancers. (Photo copyright: Gwangju Institute of Science and Technology.)

Surprising Results

Fecal material for an FMT procedure combines donated fecal matter with a sterile saline solution which is then filtered to produce a liquid solution. That solution is then administered to the recipient via colonoscopy, upper GI endoscopy, enema, or an oral capsule. The solution may also be frozen for later use.

Upon analyzing the recipients, the scientists found that six of the patients (46.2%) who had experienced resistance to immunotherapies for their cancers, benefitted from the FMTs.

“One of the most surprising results was from a [patient with] hepatocellular carcinoma who initially showed no response to the first [FMT] and continued to experience cancer progression. However, after switching the donor for the second [transplant], the patient exhibited remarkable tumor shrinkage,” co-senior study author Sook Ryun Park, MD, PhD, Assistant Professor, Asan Medical Center at the University of Ulsan College of Medicine in Seoul, told The ASCO Post, a journal of the American Society of Clinical Oncology.

“Both donors were long-lasting, good responders to anti-PD-1 inhibitors, but because we did not yet know the causative bacteria responsible for the [FMT] response, we could not predict whether the treatment would be effective,” she added.

The researchers also determined that the presence of a bacterial strain known as Prevotella merdae helped to improve the effectiveness of the FMTs, while two strains of bacteria—Lactobacillus salivarius and Bacteroides plebeius (aka, Phocaeicola plebeius)—had a detrimental impact on the transplants. 

Challenges to Widespread Adoption of FMTs

The researchers acknowledge there are challenges in widespread acceptance and use of FMTs in treating cancers but remain optimistic about the possibilities.

“Developing efficient and cost-effective methods for production and distribution is necessary for widespread adoption,” Sook Ryun Park told The ASCO Post. “Addressing these challenges through comprehensive research and careful planning will be essential for integrating FMT into the standard of care for cancer treatment.”

The research for this study was supported by grants from the Asan Institute for Life Sciences, Asan Medical Center, National Cancer Centre in Korea, the GIST Research Institute, the Bio and Medical Technology Development Program from Ministry of Science, and the Ministry of Science and ICT of the South Korean Government.

More research and clinical trials are needed before this use of FMTs can be utilized in clinical settings. However, the study does demonstrate that the potential benefits of FMTs may improve outcomes in patients with certain cancers. As this happens, microbiologists may gain a new role in analyzing the microbiomes of patients with gastrointestinal cancers.

“By examining the complex interactions within the microbiome, we hope to identify optimal microbial communities that can be used to enhance cancer treatment outcomes,” Hansoo Park told The ASCO Post. “This comprehensive approach will help us understand how the microbial ecosystem as a whole contributes to therapeutic success.”

—JP Schlingman

Related Information:

Fecal Microbiota Transplant May Help Patients with Gastrointestinal Cancers Overcome Immunotherapy Resistance

Fecal Microbiota Transplantation Improves Anti-PD-1 Inhibitor Efficacy in Unresectable or Metastatic Solid Cancers Refractory to Anti-PD-1 Inhibitor

Fecal Microbiota Transplants Can Boost the Effectiveness of Immunotherapy in Gastrointestinal Cancers

Harvard Medical School Study Finds ‘Staggering’ Amounts of Genetic Diversity in Human Microbiome; Might Be Useful in Diagnostics and Precision Medicine

Half of the genes identified were found to be singletons, unique to specific individuals, offering the possibility of developing precision medicine therapies targeted to specific patients, as well as clinical laboratory tests

Microbiologists and other medical laboratory scientists may soon have more useful biomarkers that aid in earlier, more accurate detection of disease, as well as guiding physicians to select the most effective therapies for specific patients, a key component of Precision Medicine.

Research conducted by scientists from Harvard Medical School and Joslin Diabetes Center into how individual microbial genes in human microbiome may contribute to disease risk uncovered a “staggering microbial gene diversity.”

The scientists also found that more than half of the bacterial genes examined occurred only once (called “singletons”) and were specific to each individual. A total of 11.8 million of these singletons came from oral samples and 12.6 million of them derived from gut samples, a Harvard news release noted.

In a paper published in Cell Host and Microbe the researchers state, “Despite substantial interest in the species diversity of the human microbiome and its role in disease, the scale of its genetic diversity, which is fundamental to deciphering human-microbe interactions, has not been quantified.”

To determine this quantity, the researchers conducted a meta-analysis of metagenomes from the human mouth and gut among 3,655 samples from 13 unique studies. Of their findings, they wrote, “We found staggering genetic heterogeneity in the dataset, identifying a total of 45,666,334 non-redundant genes (23,961,508 oral and 22,254,436 gut) at the 95% identity level.”

The scientists also found that while genes commonly found in all the samples seemed to drive the basic functions of a microbe’s survival, the singletons perform more specialized functions within the body, such as creating barriers to protect the micro-organisms from external onslaughts and helping to build up resistance to antibiotics. 

“Some of these unique genes appear to be important in solving evolutionary challenges,” said Braden Tierney, a PhD student at Harvard Medical School and one of the authors of the study, in the news release. “If a microbe needs to become resistant to an antibiotic because of exposure to drugs, or suddenly faces a new selective pressure, the singleton genes may be the wellspring of genetic diversity the microbe can pull from to adapt,” he concluded.

‘More Genes in the Human Microbiome than Stars in the Universe’

According to their published paper, the team of microbiologists and bioinformaticians pinpointed more than 46 million bacterial genes contained within 3,655 Deoxyribonucleic acid (DNA) samples. They identified 23,961,508 non-redundant genes in the oral samples and 22,254,436 non-redundant genes in the intestinal samples.

While similar research in the past has targeted bacteria in either the gut or the mouth, the scientists believe their study is the first that analyzed DNA collected from both areas simultaneously.

The graphic above, taken from the Harvard Medical School study, illustrates the ratio of singleton vs. non-singleton bacteria contained in human microbiome. The sheer amount of diversity seems to have impressed the scientists. “There may be more genes in the collective human microbiome than stars in the observable universe, and at least half of these genes appear to be unique to each individual,” the Harvard news release states. This diversity could lead to new precision medicine treatments and clinical laboratory diagnostics. (Graphic copyright: Harvard Medical School.)

“Just like no two siblings are genetically identical, no two bacterial strains are genetically identical, either,” said study co-author Chirag Patel, PhD, Assistant Professor of Biomedical Informatics at Harvard’s Blavatnik Institute. “Two members of the same bacterial strain could have markedly different genetic makeup, so information about bacterial species alone could mask critical differences that arise from genetic variation.”

The scientists also endeavored to determine the number of genes that reside in the human microbiome but found the precise number difficult to identify. One calculation estimated that number to be around 232 million, while another suggested the number could be substantially higher.

“Whatever it may be, we hope that our catalog, along with a searchable web application, will have many practical uses and seed many directions of research in the field of host-microbe relationships,” stated Patel in the news release.

New Diagnostics for Clinical Laboratories?

This type of research could have lasting effects on clinical laboratories. As the volume of data generated by diagnostic testing of microbes in patients opens new understanding of how these factors affect human disease and create differences from one individual to another, the increased number of genes and gene mutations mean that microbiology laboratories will increase their use of information technology and analytical software tools.

“Ours is a gateway study, the first step on a what will likely be a long journey toward understanding how differences in gene content drive microbial behavior and modify disease risk,” said Tierney in the Harvard news release.

That’s good news, because new biomarkers derived from such research will help microbiologists and other clinical laboratory scientists more accurately detect disease and identify the best therapies for individual patients. 

—JP Schlingman

Related Information:

In a First, Scientists Map the Genetic Diversity of Microbes Residing in the Human Gut and Mouth

Microbial Fingerprinting

The Universe of Microbial Genes

Duke University Study Suggests the Human Body Starves Gut Bacteria to Produce Beneficial Results

Mayo Clinic Researchers Find Some Bacteria Derail Weight Loss, Suggest Analysis of Individuals’ Microbiomes; a Clinical Lab Test Could Help Millions Fight Obesity

Researchers Discover Link between Gut Bacteria and the Effectiveness of Certain Cancer Drugs; Knowledge May Lead to New Types of Clinical Laboratory Tests

Researchers in Two Separate Studies Discover Gut Microbiome Can Affect Efficacy of Certain Cancer Drugs; Will Findings Lead to a New Clinical Laboratory Test?

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