1. Froelich, Warren

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Melanoma patients who reported eating a fiber-rich diet prior to immunotherapy lived longer without their cancer worsening than patients on a low-fiber diet, according to a study published in the journal Science (2021; doi: 10.1126/science.aaz7015). However, the study found that commercially available probiotic supplements may have unintended and potentially detrimental effects for melanoma patients undergoing immunotherapy.

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"Our newsflash from this research is it appears that dietary fiber may be very important to cancer patients starting treatment with immunotherapy," said Carrie Daniel-MacDougall, PhD, Associate Professor of Epidemiology at the University of Texas MD Anderson Cancer Center and the study's co-senior author.


"For cancer patients who are starting immunotherapy and worried about their microbiome and treatment response, I would definitely think twice before grabbing a bottle of probiotic supplements off the shelf," she added.


This latest study builds on recent human cohorts and preclinical models showing that the collective genome of microbes inhabiting the gut, known as the microbiome, likely influences a patient's chances of responding to immune checkpoint inhibitors. Jennifer Wargo, MD, Professor of Surgical Oncology and Genomic Medicine at MD Anderson, and Giorgio Trinchieri, MD, Chief of the Laboratory of Integrative Cancer Immunology at the National Cancer Institute, co-led the study with Daniel-MacDougall.


In January 2018, the MD Anderson team presented data in Science showing gut microbes can influence how melanoma patients respond to immunotherapy, particularly anti-PD-1 (programmed cell death) therapy (2018; doi: 10.1126/science.aan4236). Anti-PD-1 drugs contain an antibody that prevents activation of a brake on the immune system's T cells; when T cells are unleashed, these microbial soldiers and other parts of the immune defense system are freed to attack cancer.


Among other things, the team discovered that patients whose gut was enriched with the Ruminococcaceae family of bacteria, including the genus Faecalibacterium prausnitzii (of the Ruminococcaceae family and Clostridiales order), experienced a significantly prolonged progression-free survival (median not reached), or PFS, compared to patients with a high abundance of the Bacteriodales order of bacteria, whose PFS was impaired (median PFS of 242 days). Patients with a high diversity of bacteria in their digestive tract experienced a longer median PFS, the study added.


Analysis of fecal samples in this previous study showed that the gut microbiome of patients who responded to therapy was significantly different than non-responders. Based on these findings and the growing knowledge that the gut microbiome is shaped by usual dietary patterns and other habits, the MD Anderson research team began surveying patients' diet and supplement use and followed them for treatment outcomes.


Study Details

In this current study, the team initially profiled the gut (fecal) microbiome and assessed clinical outcomes among a large cohort of 293 patients with advanced stage melanoma treated with systemic therapy. Some 87 percent of these patients were treated with immune checkpoint blockade (ICB), most commonly PD-1 therapy.


Patients initiating therapy with ICB also were asked to participate in a lifestyle survey, which included questions about what foods they tended to eat or avoid, and whether they consumed probiotic supplements during the month prior to therapy. Low or insufficient fiber intake corresponded to less than 20 grams per day, while sufficiently high-fiber intake was defined as at or above 20 grams per day-based on patient responses to the diet questionnaire.


Patients were followed in the clinic for outcomes-namely radiographic imaging to determine tumor response to treatment-along with their median PFS.


Results showed that 37 patients meeting the threshold for a high-fiber diet had improved PFS (median not reached) compared to 91 patients with insufficient fiber intake (median 13 months). Every 5-gram increase of daily fiber intake was associated with a 30 percent lower risk of cancer progression or death.


As reported in their previous study, the fecal samples of responders contained a significantly higher abundance of Ruminococcaceae and Faecalibacterium prausnitzii in their gut than non-responders treated with PD-1. Unlike the previous study, however, the team did not observe any significant differences in overall diversity of the gut microbiota.


"Although we observed consistent signals for this family (Ruminococcaceae) of bacteria involved in breaking down starch/fiber for the host, much more research is needed," said Daniel-MacDougall in an interview. "These are 'gatekeeper' type bacteria in terms of supporting a healthy microbiome community within the host. What that means for each person is likely different. For now, our group has started clinical trials testing if we can stimulate and sustain these bacteria with dietary fiber."


When patients were further grouped according to dietary fiber intake and commercially available probiotic supplement use, a positive response to immunotherapy was seen in 18 of 22 patients (82%) who reported both high-fiber intake and no probiotic use. By comparison, an impaired response was seen in 60 of 101 (59%) patients who reported insufficient fiber intake or probiotic use. About 31 percent of late-stage melanoma patients in this cohort reported using probiotic supplements within 1 month of receiving ICB therapy.


In parallel with these observational findings, the research team conducted preclinical studies-using mouse models with melanoma tumors and fecal microbiota transplants (FMT) from responder patients-to unravel how high-fiber and probiotic use could impact therapeutic response to immune checkpoint inhibitors.


Among other things, mice fed a low-fiber diet and given common, commercially available probiotics exhibited an impaired anti-tumor response to anti-PD-1 therapy, with significantly larger tumors compared to control mice.


Analyses with flow cytometry and RNA sequencing further revealed probiotic use prior to anti-PD1 therapy was associated with lower frequency and expression of genes related to T-cell activation and interferon-gamma (IFN-gamma) response in the tumor microenvironment. A high-fiber diet was associated with slower tumor growth and significantly higher frequency of CD4+T cells in pre-clinical models treated with PD-1 inhibitors.


"Adding probiotics impaired the anti-tumor immune (T-cell) response to therapy and resulted in larger tumors when given to a mouse with a 'responder' microbiome via FMT from a responder patient," said Daniel-MacDougall. "In contrast, a high-fiber diet in the mouse was associated with an improved immune (T-cell) response in the tumor microenvironment and suppressed tumor growth, as compared to the mouse fed a low-fiber diet."


The improved immune response was defined by significantly higher T-cell activation and interferon-gamma response. T-cell infiltration and activation including IFN-gamma production-all indicators of better T-cell response-are collectively important traits of response to therapy.


Asked about the clinical implications of this study, Daniel-MacDougall said what patients are doing in terms of their dietary habits and supplement use deserved more attention as they begin their cancer journey.


"Although our findings in a carefully followed cohort of patients and pre-clinical models are quite promising, we are still working to have clearer answers to patients' questions for care teams," she said.


Future studies at MD Anderson and by other groups studying their own patients using independent methods will be needed to validate the results.


"Patients with other cancers and on other types of immunotherapy regimens want answers, too," said Daniel-MacDougall. "To provide truly definitive answers to patients and their physicians, we will have to show efficacy in clinical trials." One ongoing clinical trial of dietary fiber is being led by co-first author, Jennifer McQuade, MD, Assistant Professor of Melanoma Medical Oncology at MD Anderson.


Warren Froelich is a contributing writer.


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