ASCO 2018: Gut Microbiome Composition to Predict Resistance in Renal Cell Carcinoma Patients on Nivolumab

Chicago, IL (UroToday.com) It has been well established that the mammalian microbiota has a complex and co-evolved relationship with the immune system1. Mouse work has demonstrated that the microbiota may influence the immune effects of chemotherapy, and affect tumor control in mice treated with checkpoint blockade2,3. Recently, it has been shown in mouse models that antibiotics may compromise the efficacy of PD-1 blockade in RET melanoma and MCA-205 sarcoma models4. In that same study, a retrospective look at 248 patients with various advanced malignancies (Non-small cell lung cancer, renal cell carcinoma, urothelial cancer) found that those patients treated with antibiotics had significantly shorter PFS and OS compared to the non-antibiotic group4. These data taken together suggests that the gut microbiome significantly influences the outcome of checkpoint blockade. 


In this study, Dr. Derosa and colleagues prospectively collected stool on 65 patients from the NIVOREN study5. NIVOREN is a multicenter, open-label, non-controlled, phase II safety study in patients with metastatic renal cell carcinoma and who have progressed during or after one prior systemic anti-angiogenic treatment. Patients were classified as primary resistant or non-primary resistant based on RECIST criteria and the metagenomic data from their stool was compared between the two different cohorts. 


Of the 65 patients, 27 (39%) were classified as being resistant to nivolumab, and 42 (61%) were not resistant, based on best response. The microbiome diversity was not significantly different among the two cohorts of patients. After excluding antibiotic treated patients, Akkermansia muciniphila and Bacteroides salyersiae were more abundant in patients sensitive to nivolumab than those resistant to nivolumab. The investigators then performed fecal microbiota transplant (FMT) in immune-checkpoint inhibitor resistant RENCA mice (murine renal cell carcinoma model) and found that Akkermansia muciniphila and Bacteroides salyersiae could restore the efficacy of immune checkpoint inhibitors in a subpopulation of FMT recipients.

Prior studies have implicated Akkermansia muciniphila in various autoimmune conditions including psoriasis and type I diabetes6,7. They have also shown that coloniziation of Akkermansia muciniphila in mouse models may lead to expression of genes involved in the regulation of the immune response8. Cecal colonization by A. muciniphila resulted in up-regulation of genes involved in antigen presentation.  

Oral gut microbe cocktails, also known as “crapsules” are in development for a variety of diseases including inflammatory bowel disease and clostridium difficile9,10. It will be interesting the follow the story of the gut microbiome and its influence of cancer therapy – perhaps “crapsules” will be used in the sequence of various cancers, either prior to therapy to prime the immune system or in conjunction to maximize the effect.  

During the poster discussion session by Dr. Brian Shuch, he noted that this was the largest prospective analysis which supports the hypothesis that the gut microbiome predicts outcome to nivolumab for patients with RCC and that two future questions to consider are whether or not we should be modulating the microbiome prior to or after therapy and if we should closely regulate antibiotics, life style, and diet while on therapy. 

Presented By: Brian Shuch, MD 
Poster By: Lisa Derosa, MD, Institut de Cancérologie Gustave Roussy, Villejuif IGR 

Written by: Jason Zhu, MD Fellow, Division of Hematology and Oncology Duke University Medical Center, Twitter: @TheRealdJasonZhu at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA 

References 
1.Hooper LV, Littman DR, Macpherson AJ. Interactions Between the Microbiota and the Immune System. Science 2012;336:1268-73. 
2.Viaud S, Saccheri F, Mignot G, et al. The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide. Science 2013;342:971-6. 
3.Sivan A, Corrales L, Hubert N, et al. Commensal <em>Bifidobacterium</em> promotes antitumor immunity and facilitates anti–PD-L1 efficacy. Science 2015;350:1084-9. 
4.Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science 2017. 
5.Escudier BJ, Chabaud S, Borchiellini D, et al. Efficacy and safety of nivolumab in patients with metastatic renal cell carcinoma (mRCC) and brain metastases: Preliminary results from the GETUG-AFU 26 (Nivoren) study. Journal of Clinical Oncology 2017;35:4563-. 
6.Mithieux G. Does <em>Akkermansia muciniphila</em> play a role in type 1 diabetes? Gut 2018. 
7.LiRong T, Shuang Z, Wu Z, et al. The Akkermansia muciniphila is a gut microbiota signature in psoriasis. Experimental Dermatology 2018;27:144-9. 
8.Derrien M, van Baarlen P, Hooiveld G, Norin E, Muller M, de Vos W. Modulation of Mucosal Immune Response, Tolerance, and Proliferation in Mice Colonized by the Mucin-Degrader Akkermansia muciniphila. Frontiers in Microbiology 2011;2. 
9.Garber K. Drugging the gut microbiome. Nature Biotechnology 2015;33:228. 
10.Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing clostridium difficile infection. JAMA 2014;312:1772-8.

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