Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients
Authors: Nethanel Asher
Camila Avivi
Katerina Adler
Oren Ziv
Daniela Dick-Necula
Ronac Mamtani
Daniil Rotin
Ronnie Shapira-Frommer
Stephen Raskin
Jacob Schachter
Jennifer A Wargo
Lior Katz
Md Abdul Wadud Khan
Liat Anafi
Guy Ben-Betzalel
Gal Markel
Iris Barshack
Hagit Harati
Ilan Youngster
Nadim J Ajami
Adi Lahat
Moran Amit
Erez N Baruch
Ben Boursi
Rona Ortenberg
Naamah Bloch
Shira Ben-Simon
Omry Koren
Yael Eshet
Yael Steinberg-Silman
Jenny Melnichenko
Tal Brosh-Nissimov
Journal: Science (2021)
Discipline: Multidisciplinary
Keywords: gut microbiome; tumors; anti-PD-1 immunotherapy; clinical trial; fecal microbiota transplantation
Affiliations: The Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center, Tel-HaShomer, Israel., Department of Clinical Immunology and Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Pediatric Division and the Microbiome Research Center, Shamir (Assaf Harofeh) Medical Center, Be’er Ya’akov, Israel., School of Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Department of Gastroenterology, Sheba Medical Center, Tel HaShomer, Israel., Department of Gastroenterology, Hadassah Medical Center, Jerusalem, Israel., Department of Mathematics, Bar Ilan University, Ramat Gan, Israel., Institute of Pathology, Sheba Medical Center, Tel-HaShomer, Israel., Radiological Institute, Sheba Medical Center, Tel HaShomer, Israel., Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel., Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA., Infectious Diseases Unit, Assuta Ashdod University Hospital, Ashdod, Israel., Department of Nuclear Medicine, Sheba Medical Center, Tel HaShomer, Israel., Program for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Talpiot Medical Leadership Program, Sheba Medical Center, Tel HaShomer, Israel., Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA, USA., Department of Oncology, Sheba Medical Center, Tel HaShomer, Israel.

Abstract:  The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment. 

Retracted: No

PubPeer comments:
 Questions already asked in a [Twitter thread ] The study was planned with N=40 but why does the paper include only N=10? Was there any vancomycin only control? Was there any definition of the secondary aim  immunotherapy-favorable response? Why are there figures w o axis tick marks? ![file] Is there any independent replication? , 
 The pills were made by extracting small amounts of matter from the feces of melanoma patients who were thought to be cured and showed no evidence of the disease in imaging There have been criticisms made about using cancer patients as FMT donors. https: archive.vn 2Y4ol 1. You wouldn t expect low quality (IE: people who have had cancer) donors to be effective. 2. Even if they are effective it s likely not safe to use donors who aren t in perfect health. 3. There is no reason not to use a high quality (see: perfectly healthy, one of the fewer than 0.4% that pass this questionnaire: http: HumanMicrobiome.info FMTquestionnaire) donor. , 
 #1 Thank you for your questions. 1. We believe that the n=10 findings merit publication to support further microbiota modulation trials by other groups. Enrollment to the study continues. 2. Unfortunately there was no ABX control group, this limitation is discussed in the manuscript. 3. Increased intra-tumoral infiltration of CD8+ T-cells. 4. This is the standard Qiime2 PCA layout 5. Yes, please see Davar et al., Science 2021 ,