Rohit Thakur, PhD
Department of Surgical Oncology
The University of Texas
MD Anderson Cancer Center
Jennifer L. McQuade, MD
Department of Melanoma Medical Oncology
The University of Texas
MD Anderson Cancer Center
Jennifer A. Wargo, MD
Department of Surgical Oncology and Department of Genomic Medicine
The University of Texas
MD Anderson Cancer Center
Over the last decade, we have seen major advances in melanoma therapy and a decline in melanoma mortality.1 These advances reflect the achievements of investigators and educators around the world in improving melanoma treatment, early detection and prevention strategies.
One area that holds great promise and warrants close attention in melanoma therapy is the microbiome. Recent evidence indicates that this collection of microbes and their collective genomes that inhabit our bodies — particularly the gut microbiome — may affect host immunity and response to melanoma therapy. This has important implications, as numerous factors impact the gut microbiome, and strategies are being developed to modify it for therapeutic purposes.
The Gut Microbiome and Response to Immunotherapy
Identifying predictors of response and mechanisms of resistance to immune checkpoint blockade (ICB) therapy, as well as targets to enhance response, is an area of active investigation.2,3 The microbiome has been referred to as the second human genome,4 and several studies have demonstrated an association between the diversity and composition of the gut microbiome and response to immunotherapy.5-11
Two key studies published in 2015 demonstrated differences in response to anti-CTLA-4 and anti-PD-1 treatments in murine models, depending on the composition of the gut microbiome.5,6 These studies also showed that changing gut microbiome composition could enhance response to ICB. This work was followed by several studies in human cohorts demonstrating a link between the gut microbiome and responses to ICB.7-11 This included early work looking at associations between the gut microbiome and response to anti-CTLA-4 treatment, where distinct gut microbiome composition at baseline was associated with both an anticancer response and immune-related colitis in metastatic melanoma patients.7 Later work focused on microbiome compositional differences between patients responding or not responding to anti-PD-1 treatment with or without anti-CTLA-4 treatment, again finding distinct gut microbiome differences.8
Additionally, two studies from preclinical and human cohorts published in 2018 analyzed gut microbiome signatures in responders versus nonresponders to ICB, offering mechanistic insights on the role of the gut microbiome.9,10 Several “response-associated” taxa were identified in each of these cohorts (including Rumicococcus, Faecalibacteria and Bifidobacteria), though overlap between cohorts was admittedly modest — which may relate to different sequencing approaches used in each of the cohorts, as well as different methods of preprocessing data using different databases. Clearly, other factors could also be at play, such as diet and geographic differences.
Taken together, these studies support the premise of a link between the gut microbiome and immunity as well as the response to melanoma immunotherapy. They furthermore raise important questions. For one, can the gut microbiome be used as a diagnostic and therapeutic target in patients with melanoma and other cancers?
Factors Affecting the Gut Microbiome
Given the potential impact of microbes on response to cancer immunotherapy, we must carefully consider factors that affect the gut microbiome in patients on therapy. Environmental factors show clear predominance over genetic factors as modifiers of the gut microbiome,12 and current evidence suggests a strong role for environmental and host factors in modifying the composition, diversity and collective metabolic activities of the microbial community.
Diet and other lifestyle factors strongly affect gut microbiome composition. The impact of diet has been extensively studied in the context of gut microbiome composition, and dietary intervention is a potential therapeutic strategy to modify that composition.13 At least one dietary intervention trial is underway in melanoma patients (Table 1). It has been shown that diets high in plant-based fibers (fruits, vegetables and whole grains) and low in processed foods and added sugars, with protein sources from fish and legumes, are associated with lower cancer risk and more “favorable” microbiome and metabolic profiles.14,15 This has relevance to melanoma patients, as preliminary data presented at the 2019 annual meeting of the American Association of Cancer Research (AACR) demonstrated that melanoma patients who reported eating a high-fiber diet were more likely to respond to ICB.16
Other lifestyle factors that have been shown to impact the gut microbiota in other populations include exercise, sleep patterns and stress.13 Host factors such as age, sex and body mass index also modify gut microbiome composition.17,18 The causal relationships linking these factors with the gut microbiome are still unclear in the context of cancer, and understanding underlying mechanisms may allow better modification of the gut microbiome.
Medications may also impact the gut microbiome. This includes antibiotics, with studies demonstrating impaired responses to ICB in patients with non-small cell lung cancer who received antibiotics prior to initiation of ICB.11 Similar findings have been demonstrated in cohorts of melanoma patients.19
Numerous medications beyond antibiotics have also been shown to impact gut microbes.20 Over-the-counter supplements and probiotics may also impact the gut microbiome, with early evidence showing that patients who take over-the-counter probiotics have reduced microbiome diversity;16 thus, patient use of these compounds should be discussed and carefully considered, perhaps even discouraged outside the context of a clinical trial.
Table 1: Clinical trials of gut microbiome modulation in melanoma
|Trial number||Patient population||Intervention||Key Efficacy Endpoints||n|
|NCT03341143||metastatic melanoma patients resistant to ICB||FMT from anti-PD-1 responders via colonoscopy + anti-PD-1||ORR; immune profile change||20|
|NCT03353402||metastatic melanoma patients (cohort 1, anti-PD-1-naïve;
cohort 2, anti-PD-1-refractory)
|FMT from ICB responders via colonoscopy followed by stool capsules + anti-PD-1||engraftment and safety; immune profile change||40|
|NCT03595683||metastatic melanoma patients (Cohort 1: anti-PD-1-naïve;
Cohort 2: anti-PD1-refractory)
|EDP1503 monoclonal microbial + pembrolizumab||ORR; safety||70|
|NCT03772899||metastatic melanoma||FMT from healthy donor via stool capsules + anti-PD-1||safety, ORR, engraftment, immune profile||20|
|NCT03817125||treatment-naïve metastatic melanoma||SER-401 oral bacterial consortia + nivolumab vs. placebo + nivolumab||safety, engraftment, ORR, immune profile||30|
|NCT03819296||melanoma or genitourinary patients with refractory ICB-related colitis||FMT from healthy donor via colonoscopy||safety||100|
|NCT03934827||solid tumors presurgical resection||MRx0518 (enterococcus) oral vs. placebo 2 to 4 weeks prior
|NCT03950635||melanoma survivors||controlled feeding study of high-fiber diet or ketogenic diet||feasibility, microbiome modulation, systemic metabolism||20|
ICB = immune checkpoint blockade. FMT = fecal microbiota transplant. ORR = overall response rate.
Strategies to Modulate the Gut Microbiome
Given these findings, there is a strong interest in modulating the gut microbiome to improve therapeutic responses, and clinical trials incorporating these strategies are currently underway (Table 1). The gut microbiota can be modulated via several different approaches — including fecal microbiota transplant, administration of single bacterial strains or microbial consortia (two or more microbial groups living symbiotically), prebiotics or probiotics, targeted antibiotic approaches and other novel strategies, as well as by diet.
Fecal microbiota transplant (FMT) has perhaps generated the most provocative data thus far in microbiome modulation of patients with metastatic melanoma. FMT has been extensively studied in gastrointestinal diseases such as inflammatory bowel disease (IBD) and Clostridium difficile infection (CDI),21 and it is now being investigated in the context of cancer.22 FMT involves the transfer of fecal material from a single or multiple donors to the gastrointestinal tract of a diseased individual and has proven efficacy in certain disease settings. (For example, in refractory CDI, 80 to 90 percent of patients benefit from FMT.23)
However, FMT is still an unstandardized treatment with some risks, and therefore interventions using this approach should be performed only in the context of a carefully planned clinical trial. Such studies are currently underway (Table 1), and preliminary data from two of these studies were recently reported at the 2019 annual meeting of the AACR. Responses were observed in metastatic melanoma patients who had progressed on anti-PD-1 therapy and were subsequently treated with complete responder donor FMT and reinduction of anti-PD-1 (NCT03817125, NCT03353402). Additional trials are open and accruing patients with metastatic melanoma (Table 1). There are also data to suggest that FMT may be successful in treating immunotherapy-associated colitis.24 Two patients with this condition who were treated with FMT experienced complete resolution of clinical symptoms.24 Nonetheless, complexities exist with these approaches, and unanswered questions remain regarding optimal donors and consortia, among numerous other factors.22
Given the impact of diet on the gut microbiota, there is a strong rationale for dietary intervention trials in melanoma patients going into immunotherapy, and such trials are underway (NCT03950635). This approach holds great promise; however, long-term dietary changes are notoriously difficult to sustain, and it is unclear that such interventions will be effective in patients with widespread metastatic melanoma. Nonetheless, these interventions should be tested and incorporated into other microbiome modulation strategies (for example, with administration of FMT and specific bacterial consortia). Ultimately, they may help inform dietary recommendations to improve immunity and responses, and potentially to abrogate toxicity.
Conclusions and Future Directions
We have made major advances in melanoma therapy; however, tremendous opportunities exist for further improvement. Optimal biomarkers of response to therapy in patients with advanced disease remain elusive, and integrative approaches are needed that incorporate factors both intrinsic and extrinsic to the host.25 Additionally, we need to embrace novel trial designs (including neoadjuvant trials) and a global team scientific approach (such as that embodied in the International Neoadjuvant Melanoma Consortium). [See Neoadjuvant Therapy for Melanoma]
Microbiome modulation has shown great potential for increasing the therapeutic efficacy of ICB, but further studies are needed to define optimal strategies in clinical settings. The gut microbiome is strongly influenced by diet and other lifestyle factors; therefore, we need to consider these factors critically when developing individualized treatments. Moreover, the standardization of approaches, extensive data recording from clinical trials and global sharing of data to improve team-based research will be key in developing clinically actionable strategies to further enhance treatment (and ultimately prevention) of melanoma.
- Ward E, Sherman RL, Henley SJ, et al. Annual report to the nation on the status of cancer, 1999–2015, featuring cancer in men and women ages 20–49. JNCI 2019; 111(12).
- Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018; 359(6382):1350-1355.
- Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017; 168(4):707-723.
- Grice EA, Segre JA. The human microbiome: our second genome. Ann Rev Gen and Hum Gen 2012; 13:151-170.
- Sivan A, Corrales L, Hubert N, et al. Commensal bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 2015; 350(6264):1084-1089.
- Vetizou M, Pitt JM, Daillere R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 2015; 350(6264):1079-1084.
- Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol 2017; 28(6):1368-1379.
- Frankel AE, Coughlin LA, Kim J, et al. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia 2017; 19(10):848-855.
- Gopalakrishnan V, Spencer C, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018; 359(6371):97-103.
- Matson V, Fessler J, Bao R, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018; 359(6371):104-108.
- Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 2018; 359(6371):91-97.
- Rothschild D, Weissbrod O, Barkan E, et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 2018; 555(7695):210.
- Gilbert JA, Blaser MJ, Caporaso JG, et al. Current understanding of the human microbiome. Nat Med 2018; 24(4):392.
- Mehta RS, Nishihara R, Cao Y, et al. Association of dietary patterns with risk of colorectal cancer subtypes classified by fusobacterium nucleatum in tumor tissue. JAMA Oncol 2017; 3(7):921-927.
- Ou J, Carbonero F, Zoetendal EG, et al. Diet, microbiota, and microbial metabolites in colon cancer risk in rural Africans and African Americans. Am J Clin Nutr 2013; 98(1):111-120.
- Spencer CN, Gopalakrishnan V, McQuade J, et al. The gut microbiome (GM) and immunotherapy response are influenced by host lifestyle factors. Paper presented at: Proceedings of the 110th Annual Meeting of the American Association for Cancer Research; AACR; 2019. Abstract nr 2838/24; March 29–April 3, 2019; Atlanta.
- Biragyn A, Ferrucci L. Gut dysbiosis: a potential link between increased cancer risk in ageing and inflammaging. Lancet Oncol 2018;
- Dominianni C, Sinha R, Goedert JJ, et al. Sex, body mass index, and dietary fiber intake influence the human gut microbiome. PloS One 2015; 10(4):e0124599.
- El Elkrief A, El Raichani L, Richard C, et al. Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors. OncoImmunol 2019; 8(4):1-6.
- Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 2018; 555(7698):623.
- Ooijevaar R, Terveer E, Verspaget H, et al. Clinical application and potential of fecal microbiota transplantation. Ann Rev Med 2019; 70:335-351.
- McQuade JL, Daniel CR, Helmink BA, Wargo JA. Modulating the microbiome to improve therapeutic response in cancer. Lancet Oncol 2019; 20(2):e77-e91.
- Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. NEJM 2013; 368(5):407-415.
- Wang Y, Wiesnoski DH, Helmink BA, et al. Fecal microbiota transplantation for refractory immune checkpoint inhibitor-associated colitis. Nat Med 2018; 24(12):1804-1808.
- Cogdill AP, Andrews MC, Wargo JA. Hallmarks of response to immune checkpoint blockade. Brit J Canc 2017; 117(1):1.